The tumor microenvironment comprises various cell types and experiences dynamic alterations in physical and mechanical properties as cancer progresses. Intratumoral heterogeneity is associated with poor prognosis and poses therapeutic challenges, and recent studies have begun to identify the cellular mechanisms that contribute to phenotypic diversity within tumors. This review will describe epithelial-mesenchymal (E/M) plasticity and its contribution to phenotypic heterogeneity in tumors as well as how epigenetic factors, such as histone modifications, histone modifying enzymes, DNA methylation, and chromatin remodeling, regulate and maintain E/M phenotypes. This review will also report how mechanical properties vary across tumors and regulate epigenetic modifications and E/M plasticity. Finally, it highlights how intratumoral heterogeneity impacts therapeutic efficacy and provides potential therapeutic targets to improve cancer treatments.