The emergent field of digital pathology employing automated image analysis techniques is to revolutionize traditional pathology at the center of clinical diagnostics. Histological images provide important tumor features unavailable in molecular profiling or omics data- the spatial context of tumor and stromal cells at single-cell resolution. Methods to map the spatial and morphological patterns of cancer and normal cells can contribute to a more comprehensive understanding of the highly heterogeneous tumor microenvironment. This review focuses on methods that help expand our knowledge of intra-tumoral spatial heterogeneity of the tumor microenvironment and their potential synergies with molecular profiling technologies.