The serine-threonine kinase AKT, also known as protein kinase B (PKB), was identified in 1977 as the proto-oncogene of the v-Akt oncogenic murine thymoma virus. Subsequent research has demonstrated that genetic events activating Akt occur in most types of cancer. Activation of Akt promotes many of the processes critical to the malignant phenotype. Thus, Akt is an attractive therapeutic target for cancer. However, its critical role in many physiologic processes suggests that achieving an acceptable therapeutic index with Akt inhibitors may be a challenge. In Journal of Clinical Oncology, Yap et al report the results of, to our knowledge, the first-in-man phase I clinical trial of Akt inhibitor MK-2206. In addition to determining the maximum-tolerated dose of MK-2206, the study included a pharmacodynamic analysis of hair follicles in the majority of patients, and of paired tumor biopsies in a maximum-tolerated dose expansion cohort. The results provide strong evidence that significant inhibition of Akt is feasible in patients. However, limited single-agent antitumor activity was observed. This Understanding the Pathway report will highlight the current understanding of the role and regulation of Akt signaling in cancer and the implications for further development of therapeutic strategies against this critical signaling node. Akt is a member of the AGC family of protein kinases. Akt has three isoforms: Akt1 (also known as PKB ), Akt2 (PKB ), and Akt3 (PKB ). Akt1 and Akt2 are expressed in most tissue types; Akt3 expression is generally restricted to neuronal tissue and the testes. The three isoforms share over 80% homology and are characterized by three conserved functional domains: an amino-terminal pleckstrin homology (PH) domain that regulates intracellular trafficking of the protein, a central catalytic domain, and a carboxy-terminal regulatory domain. Activation of all three Akt isoforms is dependent on phosphatidylinositol 3-kinase (PI3K). PI3K is stimulated by a variety of signals, including growth factor and G protein–coupled receptors on the cell surface. Activation of PI3K results in the generation of 3 phosphorylated phosphatidylinositols in the cell membrane, which recruit Akt and other PH domain–containing proteins to the cell membrane. At the cell membrane, Akt comes into proximity with PDK1, another PH domain–containing serine-threonine kinase, which phosphorylates Akt at the Thr308 residue of its catalytic domain. The activated conformation of Akt is further stabilized by phosphorylation at the Ser473 residue, either by the mammalian target of rapamycin complex 2 in response to growth factor stimulation or by