Mammalian development and cell fate specification are controlled by multiple regulatory mechanisms that interact in a coordinated way to ensure proper regulation of gene expression and spatial restriction, allowing cells to adopt distinct differentiation traits and a terminal phenotype. For example, cell potency is modulated by changes in methylation that are under the control of methyltransferases and ten-eleven translocation (TET) enzymes, which establish or erase a phenotype-specific methylation pattern during embryo development and mesenchymal to epithelial transition (MET). Cell plasticity is also responsive to extracellular factors, such as small molecules that interact with cell fate definition and induce a transient pluripotent state that allows the direct conversion of an adult mature cell into another differentiated cell type. In addition, cell-secreted vesicles emerge as powerful effectors, capable of modifying cell function and phenotype and delivering different signals, such as octamer-binding transcription factor-4 (Oct4) and SRY (sex determining region Y)-box 2 (Sox2) mRNAs (implicated in the preservation of pluripotency), thus triggering epigenetic changes in the recipient cells. In parallel, mechanical properties of the cellular microenvironment and three-dimensional rearrangement can affect both cell potency and differentiation through marked effects on cytoskeletal remodelling and with the involvement of specific mechanosensing-related pathways.