Worldwide, 14 million people are diagnosed with cancer annually, and more than a quarter of these are GI cancers (more than 4 million new cases each year). Of the 8.2 million people who die as a result of cancer each year in the world, 2.7 million (33%) die as a result of GI malignancies. The total new cases of GI cancer are greater than breast (1.6 million) and lung (1.8 million) cancers combined, with 22% more deaths annually. GI cancers represent at least 10 distinct diseases (depending on how the diseases are grouped or differentiated). To some extent, many of these tumors share similar characteristics (eg, staging, and thus prognosis, for tumors in the alimentary tract considers the extent of invasion through the bowel wall as opposed to the size of the tumor, and the extent of nodal involvement), and nearly all of the GI tumors are responsive to either single-agent fluoropyrimidine or combination therapy with a fluoropyrimidine. Conversely, the biology of these tumors is distinct, as evidenced by emerging data on molecular signatures as well as variable response to treatments, particularly targeted therapies. For some GI cancers, great strides have occurred in the last 10 to 15 years in terms of understanding biology as well as expanding treatment options and improving prognosis (eg, median survival for metastatic colorectal cancer has lengthened from 1 year to nearly 3 years); however, in other GI cancers, advances have been slow and minimal in affecting the course of the disease (eg, survival for metastatic pancreatic cancers remains 1 year, and fewer than 5% of patients are long-term survivors). Our goal in this Special Series issue of Journal of Clinical Oncology is to update readers on the current state of the science for most GI cancers, break down the successes and failures, and look ahead to the potential opportunities to further advance our understanding and treatment of these diseases. In addition, we have several overview articles that have implications for multiple GI (and other) cancers and discuss issues that are critical to patient treatment. After decades of clinical trials of cytotoxic therapies that targeted rapidly dividing cells (which included a wide variety of healthy as well as cancerous cells), in the early 2000s, the era of so-called biologic or targeted therapy entered the GI cancer arena. The blockbuster development of imatinib for GI stromal tumors (GISTs) was and remains the seminal event in targeted therapies (we consider GIST a GI cancer rather than sarcoma, and it is featured in the article by Cioffia and Maki). Beyond cKIT, the focus has been on two pathways: angiogenesis via the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Initial trials in colorectal cancer were promising. In an era when clinical trials for metastatic colorectal cancer were powered to detect median overall survival improvement of as little as 2 months, Hurwitz et al presented eye-opening data on VEGF inhibition at the American Society of Clinical Oncology 2003 Annual Meeting: the addition of bevacizumab to standard cytotoxic chemotherapy improved median overall survival by nearly 5 months. Unfortunately, the magnitude of the initial results was never replicated and the expected promise of this pathway has not been realized; subsequent trials in colorectal cancer have shown only modest improvements while demonstrating a frustrating lack of efficacy in multiple other GI cancer types. Nonetheless, the VEGF pathway continues to be a valid target in GI cancers, with data emerging for other agents and other GI cancers (eg, ramucirumab and gastric cancer). The approach to a subset of lung cancers has been revolutionized with the detection of specific, targetable mutations that are drivers of cancer in some patients. Unfortunately, in GI cancers other than GIST, we have not been able to achieve such results. Nonetheless, our understanding of the molecular basis of GI cancers has expanded greatly, and it is hoped that these results will lead to a better understanding of how to characterize and treat by molecular subtypes. Data recently reported by Bass et al that have emerged from the Cancer Genomic Atlas Network have revolutionized our understanding of the pathways that lead to the development of gastric cancer, with four molecularly defined subtypes: Epstein-Barr virus positivity, microsatellite instability, chromosomal instability, or genomic stability. Similarly, the Cancer Genomic Atlas data confirmed the classification of colon and rectal cancers as emerging from either the hypermutated pathway (through high microsatellite instability, hypermethylation, MLH1 silencing, or somatic mismatch-repair gene and polymerase [POLE] mutations) or the nonhypermutated pathway (through chromosomal instability), as well as the concept that colon and rectal cancers are nearly indistinguishable molecularly. With these data, the hope is that progress in selecting the right therapy (or likely therapies) for tumors on the basis of molecular analyses may accelerate. This JCO Special Series issue begins with broad reviews of four topics that relate to multiple GI cancers: genetic screening, imaging, radiation therapy, and immunotherapy. We begin with Stoffel reviewing the role of genetics in GI cancer, discussing the variety of germline mutation syndromes that increase the risk of GI cancers, reviewing the past, current, and future methods to identify patients with genetic predispositions, and outlining the limited potential preventative strategies for high-risk patients. By intent, certain important broad-based topics that are applicable across GI cancers are not included because they have been incorporated into other JCO Special Series issues in the recent past, including Survivorship (September 2012), Pain Management (June 2014), and Geriatric Oncology JOURNAL OF CLINICAL ONCOLOGY S P E C I A L S E R I E S O V E R V I E W