Tumor progression is driven by a series of genetic and microenvironmental changes. These events lead to heterogeneous tumors which consist of a variety of cells from which some cells may possess properties which promote survival after therapy and metastasis. Recent advances in intravital microscopy (IVM) have enabled visualization of this tumor heterogeneity over time at a single-cell resolution. We highlight here the latest IVM studies that have revealed the dynamic interactions between the tumor cells and their local microenvironment. We review the most recent data that exposes how these dynamic interactions cause an additional increase in tumor heterogeneity, resulting in multiple metastatic strategies and facilitating therapy resistance.