Preclinical evaluation of drug combinations is challenging. In this mini-review we discuss the concept of synthetic lethality and how this can impact on the evaluation of drug combinations and its clinical development. We will also review novel combinations with immunologic agents and the concept of collateral lethality. We suggest that identification of synthetic lethality interactions including collateral lethality using novel drug combinations can speed up the drug development process. This approach may identify synergistic combinations in tumors with a specific molecular alteration, limiting toxicity to normal tissue. In addition, the combination of an immunotherapy with an agent targeting cancer cells have the potential for acting on different functions with no overlapping of toxicities. Here, we also discuss potential consequences of this approach in the design of early clinical studies.