Dysregulated overexpression of the anti-apoptotic proteins BCL2 is a hallmark of pathogenesis of many B-cell malignancies underpinning inappropriate survival and contributing to chemotherapy resistance. While the preclinical development of effective inhibitors has proved challenging, clinically active BCL2 antagonists are now in clinical trials, and one is approved for routine clinical use. Venetoclax (ABT-199) is a potent, orally bioavailable selective BCL2 inhibitor, now FDA and TGA-approved for relapsed chronic lymphocytic leukemia (CLL), and in Phase 1, 2 and 3 clinical trials in blood cancers. Venetoclax is highly active in patients with relapsed, refractory chronic lymphocytic leukemia (CLL), including those with del(17p) or fludarabine-refractory disease (NEJM 374:311-22, 2016); as well as in patients with relapsed mantle cell lymphoma and in some patients with follicular lymphoma and diffuse-large B cell lymphoma. Activity in acute myeloid leukaemia has also been observed. Venetoclax’s effect on cell survival is clearly observed in patients with CLL where apoptosis of CLL cells in vivo is observed within 8 hours after first exposure. The major toxicity to date has been tumour lysis, and this risk has now been mitigated through careful dose escalation. The potential potency of targeting cell survival pathways is highlighted by the observation of complete remissions in approximately 20% of patients with refractory CLL and mantle cell lymphoma, and in some AML. Preclinical and now clinical data demonstrate that venetoclax can synergise with other anti-cancer agents, and that targeting BCL2 is effective even in blood cancers lacking a functional TP53 pathway. Collectively, these data suggest that BCL2 inhibition could represent a major advance in targeted therapy for BCL2 overexpressing lymphoid cancers, either alone or in combination.