The Bruton's tyrosine kinase inhibitors (BTKis) ibrutinib and acalabrutinib have led to durable responses for patients with both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). Many patients, however, ultimately discontinue BTKis due to toxicity or progressive CLL. This article reviews the two most common reasons for ibrutinib and acalabrutinib discontinuation, including adverse events as well as CLL progression. The data for specific CLL-directed therapies following BTKi discontinuation, including venetoclax, phosphatidylinositol 3-kinase inhibitors, cellular therapies, and ongoing clinical trials, are reviewed. An evidence-based sequencing algorithm for treatment of CLL following BTKi discontinuation is proposed.