Human pp60c-Src (or c-Src) is a 60 kDa nonreceptor tyrosine kinase encoded by the SRC gene and is the cellular homologue to the potent transforming v-Src viral oncogene. c-Src functions at the hub of a vast array of signal transduction cascades that influence cellular proliferation, differentiation, motility, and survival. c-Src activation has been documented in upwards of 50% of tumors derived from the colon, liver, lung, breast, and pancreas. Therefore, a major focus has been to understand the mechanisms of c-Src activation in human cancer. Early studies concentrated on post-translational mechanisms that lead to increased c-Src kinase activity, which often correlated with overexpression of c-Src protein. More recently, the discovery of an activating SRC mutation in a small subset of advanced colon tumors has been reported. In addition, elevated SRC transcription has been identified as yet another mechanism contributing significantly to c-Src activation in a subset of human colon cancer cell lines. Interestingly, histone deacetylase (HDAC) inhibitors, agents with well-documented anti-cancer activity, repress SRC transcription in a wide variety of human cancer cell lines. Analysis of the mechanisms behind HDAC inhibitor mediated repression could be utilized in the future to specifically inhibit SRC gene expression in human cancer.