A successful ADC is the one that works well in cancer patients with unmet medical needs where current approved therapies either work poorly or patients have become resistant or refractory to them. An ideal ADC should be highly internalized with high lysosomal trafficking in multiple tumor types with varying degree of the antigen expression. Additionally, it should exert a rapid and sustained tumor killing (either PR or CR) with better tolerability than the chemotherapeutics or radiation treatment or other targeted therapies. In cancer treatment, combinations of potential cancer therapeutics with different MOAs of tumor killing or disease control is very common. Ideally, all ADCs could be combined with the agents that have been traditionally combined with cytotoxic chemotherapeutic agents. However, given the low TI, steep threshold for DLTs of the most ADCs, the toxicity remains an important criteria in deciding which therapies could be combined. ADCs with good safety and sustained activity following repeated cycles of ADC treatment are the best candidates for combinations with other chemotherapies, targeted agents and radiation. With the success of immune-oncology agents, including immune checkpoint inhibitors of PD-1:PD-L1 axis, CAR-T cell therapies, it is not surprising that nearly all clinical stage ADCs are being combined with cancer immunotherapy agents to boost the anti-tumor responses. But it is imperative that mechanism based combinations are employed with ADCs. If the candidate ADC is unable to induce immunogenic cell death or increase tumor mutational burden or activation of the immune system, it would be counter-intuitive to combine the candidate ADC with cancer immunotherapy agents.