Venetoclax is the first specific BCL2 inhibitor shown to have efficacy in the treatment of B cell malignancies in particular chronic lymphocytic leukaemia (CLL). CLL is the most common leukaemia affecting adults in western populations and when relapsed or refractory to front line chemo-immunotherapy carries with it a relatively poor prognosis especially if associated with high risk genetic features such as TP53 dysfunction. CLL ubiquitously overexpresses BCL2 rendering it resistant to apoptotic cell death, over time this results in inappropriate accumulation of the malignant clone in the bone marrow, peripheral blood and lymph node compartments. By inhibiting BCL2 and inducing apoptosis venetoclax has achieved response rates of 80% including complete response rates of 20% among patients with high risk relapsed and refractory CLL. The Achilles heel of venetoclax treatment however, is secondary clinical resistance, emerging results from combination therapy with monoclonal antibodies and other novel targeted agents such as Burton’s tyrosine kinase inhibitors are associated with deeper clinical responses and prolonged progression free survival. However inhibition of BCL2 has wide ranging effects on the immunological milieu. Whilst malignant cells are more susceptible to venetoclax induced apoptosis, non-malignant B cells, and conventional T cells are also reduced by treatment. Interestingly, innate T cell populations and immature NK cells exhibit preferential survival. This may have consequences for the combination of venetoclax with immunotherapies.