Ovarian cancer, primarily the epithelia-origin high-grade serous (HGS) type, is one of the most lethal gynecological malignancies. Clinically, over 75% of newly diagnosed HGS ovarian cancer patients carry stage III-IV diseases, and have less than 33% survival rate over a 5-year span. Current treatment of such aggressive disease remains largely dependent on two types of chemotherapeutic drugs: Taxane- and platinum-based agents. Thus, there is an imminent need for the improvement in the detection, diagnostic modalities and target-based therapies against this malignant disease. The majorities of HGS ovarian tumors exhibit mutational inactivation or loss of p53 and/or BRCA1/BRCA2 genes, thereby conferring strong genomic instabilities. As such, currently available target–based therapies, such as inhibitors targeting ErbB receptors or Raf/Ras/MAPK- or PI3k/Akt-dependent oncogenic pathways, display limited efficacy against HGS ovarian cancer. Our recent study suggests that the malignancy of this aggressive disease, at least in part, is regulated by CD151 and its associated laminin-binding (LB) integrins. Our clinical, functional and xenograft analyses consistently indicate that in contrast to prior reports on the RGD-based integrins, CD151-LB integrin complexes play a strong suppressive role in ovarian tumorigenesis and metastatic progression. In this short review/commentary, we will briefly summarize our current understanding of integrin function and signaling in ovarian cancer. We will discuss the emerging clinical significance and functional roles of CD151-LB integrin complexes in this disease. Finally, we will provide an outlook of how studies of CD151-integrin complexes may shape our understanding of ovarian cancer aggressiveness and facilitate the development of effective biomarkers and therapeutic targets.