The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease. Venetoclax has also demonstrated efficacy in other B-cell non-Hodgkin lymphoma subtypes, in particular mantle cell lymphoma and follicular lymphoma. Here, I review the history of targeting BCL-2 in B-cell lymphomas, and I discuss recent data on venetoclax used as monotherapy and in combination with monoclonal antibodies, chemotherapy, and other novel agents. I also discuss how genomic and functional approaches such as BH3 profiling may allow us to prioritize novel-agent combinations for further study in clinical trials. These approaches may also help us to understand resistance mechanisms to BCL-2–selective therapy and how to overcome resistance. Finally, I provide my perspective on how to move BCL-2–directed therapies forward toward a goal of developing well-tolerated, time-limited combination regimens with curative potential for patients with B-cell lymphomas.