While mutations resulting in the chronic activation of signaling pathways drive human cancer, the epigenetic state of a cell ultimately dictates the biological response to any given oncogenic signal. Moreover, large-scale genomic sequencing efforts have now identified a plethora of mutations in chromatin regulatory genes in human tumors, which can amplify, modify, or complement traditional oncogenic events. Nevertheless, the co-occurrence of oncogenic and epigenetic defects appears to create novel therapeutic vulnerabilities, which can be targeted by specific drug combinations. Here we discuss general mechanisms by which oncogenic and epigenetic alterations cooperate in human cancer and synthesize the field's early efforts in developing promising therapeutic combinations. Collectively, these studies reveal common themes underlying potential chemical synthetic lethal interactions and support both the expansion and refinement of this type of therapeutic approach.