Abstract: Chronic lymphocytic leukemia (CLL) is a prevalent but incurable malignancy with a variable disease course. As the most common lymphoid malignancy in the United States, CLL management often involves a watch-and-wait approach for asymptomatic patients, with treatment options guided by clinical and genetic factors. The landscape of CLL treatment has been significantly transformed by the introduction of targeted therapies (TT) since 2014, including Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib, phosphoinositide 3 kinase (PI3K) inhibitors like idelalisib, and B-cell lymphoma-2 (BCL-2) inhibitors such as venetoclax. This study examines the adoption of TT compared to traditional chemotherapy and chemoimmunotherapy (CT/CIT) for first-line (1L) treatment of CLL within the Veterans Affairs (VA) healthcare system. Utilizing retrospective electronic medical record data from VA facilities from January 1, 2014, to December 31, 2021, we analyzed treatment trends among 5,175 patients. Results indicate a notable shift from CT/CIT to TT over the study period, with a decline in the use of ibrutinib and an increase in the adoption of venetoclax, acalabrutinib, and zanubrutinib. This shift highlights the rapid evolution of treatment paradigms in CLL, influenced by the introduction of novel targeted therapies and underscores the importance of timely implementation of new treatment options in clinical practice.