Background and Purpose Antibody-drug conjugates (ADCs) represent a therapeutic modality that guides chemotherapies to tumoral cells by using antibodies against tumor associated antigens (TAAs). The antibody and the chemotherapy or payload are attached by a chemical structure called the linker. The strategy for the development of this type of drugs was based on several rational pillars, including the use of a very potent payload and the use of specific antibodies acting only on antigens expressed on tumoral cells. Experimental Approach In this article, by using data from all approved ADCs that have received regulatory approval, we explore the contribution of each ADC component to clinical activity. Key Results We have identified that the potency of the payload and its amount -evaluated by the drug to antibody ratio (DAR)- do not relate to clinical efficacy. Additionally, some ADCs have been developed against antigens expressed in non-transformed tissues producing clinical activity, suggesting that TAA specificity is not a mandatory requirement. Finally, we observed that ADCs with payloads harboring more favorable physicochemical characteristics showed the greater activity, and indeed were those that used linkers with site-specific conjugation. Conclusion and Implications Based on currently available data, our study provides insights as to the best way to develop novel ADCs in the future.