Molecular profiling of cancer patients and modelling of human cancer in mice revealed cell type and tissue-specific differences in tumor development and evolution. However, the context-dependent determinants of cancer remain poorly understood. A systematic characterization of the biological underpinnings of context-specificity will, therefore, be pivotal to design more effective therapies. In this review article, we focus on recent advances on molecular, cellular and microenvironmental aspects of context-dependency. We highlight new strategies to study this phenomenon in tumorigenesis and tumor evolution. Notably, we elucidate tissue and cell type-specific signaling cues as well as tumor microenvironment niches, using novel next-generation dual and triple recombinase-based mouse models of cancer.