<p>Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for relapsed or refractory hematologic malignancies, producing high remission rates in otherwise treatment-resistant patients. However, primary resistance and disease relapse remain common, particularly in solid tumors, limiting long-term benefit and broader clinical applicability. As the population of patients failing therapy grows, there is an urgent need for an integrated understanding of resistance mechanisms and a structured approach to salvage therapy. This review proposes a conceptual “Why-How-What if” framework to navigate the complexities of treatment failure. We first address “Why” therapy fails, identifying multifactorial drivers including tumor-intrinsic factors like antigen loss and immune evasion, T cell-intrinsic dysfunction such as exhaustion and limited persistence, and extrinsic constraints imposed by an immunosuppressive tumor microenvironment. We then explore “How” to enhance efficacy through mechanism-based strategies. These include rational combination approaches with immune checkpoint inhibitors or small molecule inhibitors, and next-generation engineering such as dual-target, armored, and in vivo generated CAR-T cells aimed at overcoming metabolic and physical barriers. Finally, we address the “What if” of treatment failure by summarizing individualized salvage options, for which current clinical evidence is derived predominantly from hematologic malignancies. These strategies range from target-switching and bispecific antibodies to emerging cellular platforms like CAR-natural killer cells and consolidation via allogeneic hematopoietic stem cell transplantation. By integrating mechanisms of failure with evolving optimization and salvage strategies, this framework provides a practical roadmap for clinical and translational progress. Future success will depend on biomarker-guided combinations and the continued diversification of adoptive cell therapy platforms.</p>