Venetoclax is a B cell lymphoma 2 (BCL-2)-selective antagonist used to treat chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Although this has been a promising therapeutic option for these patients, many of these patients develop resistance and relapsed disease. Here, we summarize the emerging mechanisms of resistance to venetoclax treatment, discuss the promising combination strategies, and highlight the combinations that are currently in clinical trials. Efforts to understand mechanisms of resistance are critical to advance the development of new targeted therapeutic strategies and further our understanding of the biological functions of BCL-2 in tumor cells.