The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations demonstrated a synergistic antitumor effect through multiple mechanisms, providing a robust foundation for translating this regimen into clinical trials. Beyond the dual inhibition by 2 small molecules, another innovative concept being tested with this combination is the use of measurable residual disease (MRD)-driven treatment vs fixed-duration treatment to meet the escalating demand for oral, convenient, cost-effective, and time-limited therapeutic approaches. The clinical translation of this combination has yielded remarkable outcomes with significant improvements in the progression-free survival and overall survival rates for both treatment-naïve patients and those with relapsed/refractory CLL. Notably, a substantial proportion of patients achieved undetectable MRD. Clinical trial updates following the initial published results have shown consistency and durability of responses over time. In this review, the initial investigator-initiated trial results for ibrutinib and venetoclax are discussed, several multicenter clinical trial designs and outcomes are examined, variables such as chromosome 17p deletion that influence treatment responses are addressed, and the safety of the regimen is discussed. In addition, we reviewed the usage of this combination in other B-cell malignancies and discussed how current knowledge can be used for shaping the future CLL treatment regimens.