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Immunotherapy has transformed the therapeutic landscape of cancer, but the preclinical evaluation of combination approaches that will deepen and broaden its clinical benefit has lagged far behind due to the lack of expedient and easily accessible ex vivo human systems. In this issue, Jenkins and colleagues and Deng and colleagues report the use of organotypic cultures of tumors derived from mice and humans containing both tumor cells and cells from their local immune microenvironment to recapitulate the in vivo use of immune checkpoint inhibitors and extend the application of this system to therapeutic combinations of immune checkpoint blockade and molecularly targeted agents. Cancer Discov; 8(2); 143-5. ©2018 AACR.See related article by Jenkins et al., p. 196See related article by Deng et al., p. 216.