Volume imaging visualizes the three-dimensional (3D) complexity of tumors to unravel the dynamic crosstalk between cancer cells and the heterogeneous landscape of the tumor microenvironment (TME). Tissue clearing and intravital microscopy (IVM) constitute rapidly progressing technologies to study the architectural context of such interactions. Tissue clearing enables high-resolution imaging of large samples, allowing for the characterization of entire tumors and even organs and organisms with tumors. With IVM, the dynamic engagement between cancer cells and the TME can be visualized in 3D over time, allowing for acquisition of 4D data. Together, tissue clearing and IVM have been critical in the examination of cancer-TME interactions and have drastically advanced our knowledge in fundamental cancer research and clinical oncology. This review provides an overview of the current technical repertoire of fluorescence volume imaging technologies to study cancer and the TME, and discusses how their recent applications have been utilized to advance our fundamental understanding of tumor architecture, stromal and immune infiltration, vascularization and innervation, and to explore avenues for immunotherapy and optimized chemotherapy delivery.