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Simple Summary: Phenotypic diversity in tumors makes treatment difficult and leads to poor prognosis. A better understanding of what causes intratumoral heterogeneity and differences in cells that are within the same tumor will advance therapeutic options and improve patient outcomes. This review will summarize recent studies that have examined the various cancer cell phenotypes along the epithelial–mesenchymal spectrum present in tumors and how epigenetic factors and the mechanical properties of tumor tissue mediate these phenotypes. This review will also discuss the therapeutic implications of intratumoral heterogeneity, such as drug resistance and tumor recurrence, and highlight opportunities to address current limitations in cancer treatments. 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. [ABSTRACT FROM AUTHOR]