Venetoclax is a first-in-class, orally bioavailable, and highly selective BCL-2 inhibitor. It has transformed the therapeutic landscape of hematologic malignancies by targeting the anti-apoptotic pathway in malignant cells. Its rational development followed the limitations of earlier BCL-2 inhibitors, such as navitoclax, which showed off-target BCL-XL inhibition and caused dose-limiting thrombocytopenia. Venetoclax demonstrates predictable pharmacokinetics, favourable tolerability, and efficacy across lymphoid and myeloid cancers. In chronic lymphocytic leukaemia (CLL), venetoclax-based regimens—particularly venetoclax-rituximab and venetoclax-obinutuzumab—have produced deep molecular remissions, high rates of undetectable minimal residual disease, and durable progression-free survival in both relapsed and frontline settings. Combination strategies of venetoclax with BTK inhibitors have enabled time-limited, chemotherapy‑free, and all oral treatment options Repurposing venetoclax for acute myeloid leukaemia (AML) has been a major therapeutic advancement. The VIALE‑A and VIALE‑C trials established venetoclax with hypomethylating agents or low‑dose cytarabine as the standard of care for older or unfit AML patients, with significant improvements in remission rates and overall survival. Emerging evidence supports its use in younger AML patients, with comparable or superior efficacy to intensive chemotherapy and markedly reduced early mortality. Dose-modification strategies, including low-dose venetoclax with azole prophylaxis or shortened treatment duration, offer practical solutions to reduce toxicity in real-world settings. Beyond CLL and AML, venetoclax has demonstrated clinically meaningful activity in multiple myeloma with t(11;14), mantle cell lymphoma, lymphoplasmacytic lymphoma, T‑ALL, and select high‑risk lymphomas. Its expanding role across hematologic malignancies reflects a strong mechanistic rationale, synergistic potential with partner drugs, and a favourable therapeutic index.