Prevailing evidence has established the fundamental role of microenvironmental conditions in tumorigenesis. However, the ability to identify, interrupt, and translate the underlying cellular and molecular mechanisms into meaningful therapies remains limited, due in part to a lack of organotypic culture systems that accurately recapitulate tumor physiology. Integration of tissue engineering with microfabrication technologies has the potential to address this challenge and mimic tumor heterogeneity with pathological fidelity. Specifically, this approach allows recapitulating global changes of tissue-level phenomena, while also controlling microscale variability of various conditions including spatiotemporal presentation of soluble signals, biochemical and physical characteristics of the extracellular matrix, and cellular composition. Such platforms have continued to elucidate the role of the microenvironment in cancer pathogenesis and significantly improve drug discovery and screening, particularly for therapies that target tumor-enabling stromal components. This review discusses some of the landmark efforts in the field of micro-tumor engineering with a particular emphasis on deregulated tissue organization and mass transport phenomena in the tumor microenvironment.