This review provides an overview of the evolution and advancements in antibody-drug conjugates (ADCs) since their first approval in 2000. ADCs have revolutionized targeted cancer therapy, particularly for advanced-stage cancers, by delivering highly potent cytotoxic payloads to tumor cells via tumor-selective monoclonal antibodies. The review highlights the key components of ADCs, including the antibody, payload, and linker, and discusses their mechanisms of action. It emphasizes the importance of target antigen selection, antibody internalization, and payload diversity in optimizing ADC efficacy and safety. Recent trends in ADC development, such as the use of non-internalizing ADCs targeting stromal components and immune-stimulating payloads, are also discussed. The review addresses current challenges, including toxicity, drug resistance, and complex pharmacokinetics, and outlines future directions for improving ADC design and performance. The authors conclude that the dynamic evolution of ADC technology holds promise for personalized cancer treatment, with ongoing research aimed at enhancing therapeutic indices and tolerability.This review provides an overview of the evolution and advancements in antibody-drug conjugates (ADCs) since their first approval in 2000. ADCs have revolutionized targeted cancer therapy, particularly for advanced-stage cancers, by delivering highly potent cytotoxic payloads to tumor cells via tumor-selective monoclonal antibodies. The review highlights the key components of ADCs, including the antibody, payload, and linker, and discusses their mechanisms of action. It emphasizes the importance of target antigen selection, antibody internalization, and payload diversity in optimizing ADC efficacy and safety. Recent trends in ADC development, such as the use of non-internalizing ADCs targeting stromal components and immune-stimulating payloads, are also discussed. The review addresses current challenges, including toxicity, drug resistance, and complex pharmacokinetics, and outlines future directions for improving ADC design and performance. The authors conclude that the dynamic evolution of ADC technology holds promise for personalized cancer treatment, with ongoing research aimed at enhancing therapeutic indices and tolerability.