Antibody–drug conjugates (ADCs) have evolved significantly since their first approval in 2000, transforming cancer treatment by offering targeted therapy with improved therapeutic index and tolerability. ADCs consist of a tumor-selective monoclonal antibody (mAb) linked to a potent cytotoxic payload via a stable linker, enabling selective delivery of the toxin to cancer cells. Recent advancements in ADC design, including novel conjugation technologies, payload diversity, and improved linker stability, have expanded their applications to a broader range of cancers, including those with heterogeneous antigen expression. The mechanism of action involves internalization of the ADC by cancer cells, followed by release of the cytotoxic payload, which induces cell death through various pathways, including bystander killing. Additionally, the mAb component can engage immune cells, enhancing antitumor immunity. However, challenges such as toxicity, drug resistance, and off-target effects remain. Next-generation ADCs aim to overcome these issues through site-specific conjugation, improved payload design, and enhanced linker stability. Despite these advancements, factors such as antigen expression, endocytic efficiency, and payload pharmacokinetics continue to influence ADC efficacy. The development of non-internalizing ADCs targeting tumor microenvironment components and the integration of immune-stimulating payloads represent promising directions. Overall, ADCs are poised to become a cornerstone of personalized cancer therapy, with ongoing research aimed at improving their safety, efficacy, and applicability across diverse cancer types.Antibody–drug conjugates (ADCs) have evolved significantly since their first approval in 2000, transforming cancer treatment by offering targeted therapy with improved therapeutic index and tolerability. ADCs consist of a tumor-selective monoclonal antibody (mAb) linked to a potent cytotoxic payload via a stable linker, enabling selective delivery of the toxin to cancer cells. Recent advancements in ADC design, including novel conjugation technologies, payload diversity, and improved linker stability, have expanded their applications to a broader range of cancers, including those with heterogeneous antigen expression. The mechanism of action involves internalization of the ADC by cancer cells, followed by release of the cytotoxic payload, which induces cell death through various pathways, including bystander killing. Additionally, the mAb component can engage immune cells, enhancing antitumor immunity. However, challenges such as toxicity, drug resistance, and off-target effects remain. Next-generation ADCs aim to overcome these issues through site-specific conjugation, improved payload design, and enhanced linker stability. Despite these advancements, factors such as antigen expression, endocytic efficiency, and payload pharmacokinetics continue to influence ADC efficacy. The development of non-internalizing ADCs targeting tumor microenvironment components and the integration of immune-stimulating payloads represent promising directions. Overall, ADCs are poised to become a cornerstone of personalized cancer therapy, with ongoing research aimed at improving their safety, efficacy, and applicability across diverse cancer types.