Cancer therapy evolved from cytotoxic chemotherapy to targeted and immune treatments guided by molecular profiling. Early cytotoxic drugs, rooted in mustard-gas observations, remain effective but toxic. Targeted agents exploit oncogenic vulnerabilities yet commonly select resistant clones. Checkpoint inhibitors and engineered modalities (ADCs, BiTEs, CAR-T) yield responses but are limited by toxicity and adaptive antigen loss. Future treatment combinations will require targeting the evolution of resistance.