Targeted therapies for chronic lymphocytic leukemia (CLL) include venetoclax, the oral inhibitor of B cell lymphoma-2 (BCL2), and inhibitors of kinases in the B cell receptor signaling pathway, like Bruton's tyrosine kinase (BTK) and PI3-kinase. Randomized clinical trials clearly demonstrated improved progression-free survival with targeted therapy over chemoimmunotherapy in first-line and treatment for relapsed/refractory CLL. Comparative trials of venetoclax-based versus other targeted therapies have not been conducted. Differentiating features and considerations with targeted therapies include goals of treatment and therapeutic approach as well as side-effect and toxicity profiles. With targeted therapy options for first-line and relapsed CLL, it is ever more important to develop sound rationale and strategy for selecting first-line and treatment for relapsed disease and for long-term management of the disease, including therapeutic sequencing. Fixed-duration therapy with a treatment-free remission is a particularly appealing prospect since it avoids continuous exposure to treatment and potential for toxicity. We discuss rationale and practical application of venetoclax in first-line and treatment for relapsed and refractory CLL. Venetoclax is highly active at achieving deep remission for most treated patients with CLL, including those with high-risk disease such as del(17p) CLL.