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Critical cancer mutations are often regional and mosaic, confounding the efficacy of targeted therapeutics. Single cell mRNA sequencing (scRNA-seq) has enabled unprecedented studies of intra-tumor heterogeneity and its role in cancer progression, metastasis, and treatment resistance. When coupled with DNA sequencing, scRNA-seq allows one to infer the in vivo impact of genomic alterations on gene expression. This combination can be used to reliably distinguish neoplastic from non-neoplastic cells, to correlate paracrine-signaling pathways between neoplastic cells and stroma, and to map expression signatures to inferred clones and phylogenies. Here we review recent advances in scRNA-seq, with a special focus on cancer. We discuss the challenges and prospects of combining scRNA-seq with DNA sequencing to assess intra-tumor heterogeneity.