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Chronic lymphocytic leukaemia (CLL) constitutively overexpresses B-cell lymphoma 2 (BCL2) with consequent dysregulation of intrinsic apoptosis leading to abnormal cellular survival. Therapeutic use of BCL2 inhibitors (BCL2i, eg, venetoclax) in CLL, as both continuous monotherapy or in fixed duration combination, has translated scientific rationale into clinical benefit with significant rates of complete responses, including those without detectable minimal residual disease. Unlike with chemotherapy, response rates to venetoclax do not appear to be influenced by pre-existing chromosomal abnormalities or somatic mutations present, although the duration of response observed remains shorter for those with traditional higher risk genetic aberrations. This review seeks to describe both the disease factors that influence primary venetoclax sensitivity/resistance and those resistance mechanisms that may be acquired secondary to BCL2i therapy in CLL. Baseline venetoclax-sensitivity or -resistance is influenced by the expression of BCL2 relative to other BCL2 family member proteins, microenvironmental factors including nodal T-cell stimulation, and tumoral heterogeneity. With selection pressure applied by continuous venetoclax exposure, secondary resistance mechanisms develop in oligoclonal fashion. Those mechanisms described include acquisition of BCL2 variants, dynamic aberrations of alternative BCL2 family proteins, and mutations affecting both BAX and other BH3 proteins. In view of the resistance described, this review also proposes future applications of BCL2i therapy in CLL and potential means by which BCL2i-resistance may be abrogated.