Outcomes of and challenges in therapy with covalent and noncovalent BTKi for CLL. Patients with CLL at diagnosis are expected to have BTK^WT disease. When it is treated with covalent BTKi, 3 different outcomes [1], [2], and [3] are observed. [1] The majority of patients have a clinical response, their BTK^WT status is presumed to be maintained, and they continue to receive covalent BTKi until discontinuation or disease progression (DP). [2] About 15-20% of patients are intolerant to covalent BTKi and discontinue therapy. Their BTK^WT status is maintained, but they need treatment with other agents. When given noncovalent BTKi, they either respond to noncovalent BTKi and continue therapy or develop new non-C481 BTK mutations or presumably non-BTK mutations and need new therapeutics. [3] About 10-15% of patients have DP owing to BCR pathway mutation, with replacement of the cysteine residue in C481 (such as C481S and C481R) being the most prevalent substitution. When given noncovalent BTKi, they have responses and even sometimes experience resolution of the initial C481 (C481S) mutant clone. However, some of these patients have DP owing to development of a second-site (non-C481) mutant clone and clonal expansion. These new clones do not respond to treatment with covalent or noncovalent BTKi, and novel approaches are required for them. Rx, therapy; cBTKi, covalent BTK inhibitor; ncBTKi, noncovalent BTK inhibitor; WT, wild-type; mt, mutant.