Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by CD19, CD5, CD20, and CD23 expression. It predominantly affects the elderly and has a high prevalence in North America, Europe, and Oceania. Recent advancements in CLL treatment have focused on targeting B-cell lymphoma 2 (BCL2) and Bruton's kinase (BTK). However, resistance to BTK inhibitors like ibrutinib and BCL2 inhibitors like venetoclax, along with adverse effects and Richter's transformation, has led to the emergence of double-refractory CLL, where patients are resistant to both therapies. This review discusses the mechanisms of resistance to ibrutinib and venetoclax, as well as innovative treatment approaches for double-refractory CLL. BTK inhibitors work by inhibiting BTK signaling, which is crucial for B-cell survival and proliferation. Resistance often involves mutations in BTK or phospholipase C gamma 2 (PLCG2), reducing drug affinity. Venetoclax resistance can result from mutations in BCL2 or increased reliance on other anti-apoptotic proteins like MCL1 or BCL-XL. Combination therapy with BTK and BCL2 inhibitors has shown promise, as preclinical studies suggest synergy. Non-covalent BTK inhibitors, such as pirtobrutinib, and other novel agents like BCL2 inhibitors, PROTACs, and bispecific T-cell engagers (BiTEs) are being evaluated for double-refractory CLL. CAR-T and CAR-NK cell therapies, as well as allogeneic hematopoietic stem cell transplantation (alloHCT), are also being explored. Despite these advancements, challenges remain in selecting the most effective treatment for double-refractory CLL, and further research is needed to optimize therapeutic strategies.Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by CD19, CD5, CD20, and CD23 expression. It predominantly affects the elderly and has a high prevalence in North America, Europe, and Oceania. Recent advancements in CLL treatment have focused on targeting B-cell lymphoma 2 (BCL2) and Bruton's kinase (BTK). However, resistance to BTK inhibitors like ibrutinib and BCL2 inhibitors like venetoclax, along with adverse effects and Richter's transformation, has led to the emergence of double-refractory CLL, where patients are resistant to both therapies. This review discusses the mechanisms of resistance to ibrutinib and venetoclax, as well as innovative treatment approaches for double-refractory CLL. BTK inhibitors work by inhibiting BTK signaling, which is crucial for B-cell survival and proliferation. Resistance often involves mutations in BTK or phospholipase C gamma 2 (PLCG2), reducing drug affinity. Venetoclax resistance can result from mutations in BCL2 or increased reliance on other anti-apoptotic proteins like MCL1 or BCL-XL. Combination therapy with BTK and BCL2 inhibitors has shown promise, as preclinical studies suggest synergy. Non-covalent BTK inhibitors, such as pirtobrutinib, and other novel agents like BCL2 inhibitors, PROTACs, and bispecific T-cell engagers (BiTEs) are being evaluated for double-refractory CLL. CAR-T and CAR-NK cell therapies, as well as allogeneic hematopoietic stem cell transplantation (alloHCT), are also being explored. Despite these advancements, challenges remain in selecting the most effective treatment for double-refractory CLL, and further research is needed to optimize therapeutic strategies.