Selection of Bruton’s tyrosine kinase (BTK) inhibitor therapy in CLL patients requires recognizing key differences between first- and next-generation agents in terms of the safety profile and efficacy across all patient types, including patients with high-risk features. Newer BTK inhibitors with greater kinase selectivity have shown fewer off-target adverse effects and allowed patients to switch BTK inhibitors with continued clinical benefit, fewer recurrences, and lower severity.