The article reviews the challenges and treatment options for patients with double-refractory chronic lymphocytic leukemia (CLL), a condition where patients have previously responded to both BTK inhibitors and BCL2 inhibitors but have since relapsed. The authors discuss the mechanisms of resistance to ibrutinib and venetoclax, the most commonly used BTK and BCL2 inhibitors, respectively. They highlight the importance of mutations in BTK and PLCG2 in ibrutinib resistance, while venetoclax resistance is driven by point mutations reducing binding affinity and upregulation of other anti-apoptotic proteins. The combination of ibrutinib and venetoclax has shown promise in clinical trials, particularly in high-risk patients, and non-covalent BTK inhibitors like pirtobrutinib and nemabrutinib are effective alternatives. Other treatment options, including PI3K inhibitors, BTK degraders, bispecific T-cell engagers (BiTEs), chimeric antigen receptor-positive T (CAR-T) and NK (CAR-NK) cell therapy, and allogenic hematopoietic stem cell transplantation (alloHCT), are also explored. The article concludes by emphasizing the need for further clinical trials to determine the most effective strategies for treating double-refractory CLL.The article reviews the challenges and treatment options for patients with double-refractory chronic lymphocytic leukemia (CLL), a condition where patients have previously responded to both BTK inhibitors and BCL2 inhibitors but have since relapsed. The authors discuss the mechanisms of resistance to ibrutinib and venetoclax, the most commonly used BTK and BCL2 inhibitors, respectively. They highlight the importance of mutations in BTK and PLCG2 in ibrutinib resistance, while venetoclax resistance is driven by point mutations reducing binding affinity and upregulation of other anti-apoptotic proteins. The combination of ibrutinib and venetoclax has shown promise in clinical trials, particularly in high-risk patients, and non-covalent BTK inhibitors like pirtobrutinib and nemabrutinib are effective alternatives. Other treatment options, including PI3K inhibitors, BTK degraders, bispecific T-cell engagers (BiTEs), chimeric antigen receptor-positive T (CAR-T) and NK (CAR-NK) cell therapy, and allogenic hematopoietic stem cell transplantation (alloHCT), are also explored. The article concludes by emphasizing the need for further clinical trials to determine the most effective strategies for treating double-refractory CLL.