Purpose of Review <p>Targeted therapies have revolutionized the treatment of chronic lymphocytic leukemia (CLL), however the disease remains incurable. This is largely due to somatic mutations in proteins targeted by these therapies, like Bruton’s tyrosine kinase (BTK) and B cell lymphoma-2 (Bcl-2), or transcriptional rewiring of CLL cells. Here we review recent findings regarding mechanisms of resistance to targeted agents in CLL.</p> Recent Findings <p>BTK inhibitor (BTKi) resistant CLL is potentiated by mutations disrupting covalent and non-covalent BTKi binding or those conferring loss of BTK’s kinase activity. Point mutations in Bcl-2 impact the efficacy of Bcl-2 inhibitor venetoclax, however cells employ a diverse variety of mechanisms to escape venetoclax-induced apoptosis. These mechanisms function through AKT and result in increased dependency on and stabilization of other antiapoptotic Bcl-2 family members as well as disruption of BAK/BAX pore formation.</p> Summary <p>Recent work in CLL has pinpointed mechanisms hijacked by cells to abrogate treatment efficacy. Ongoing research efforts are focused on the advent of next-generation inhibitors and protein degraders to circumvent resistance. Such studies will prove invaluable in providing CLL patients with a diverse repertoire of therapeutic options following relapse.</p>