During embryonic development, cells become gradually restricted in their developmental potential and start elaborating lineage‐specific transcriptional networks to ultimately acquire a unique differentiated state. Hox genes play a central role in specifying regional identities, thereby providing the cell with critical information on positional value along its differentiation path. The exquisite DNA‐binding specificity of the Hox proteins is frequently dependent upon their interaction with members of the TALE family of homeodomain proteins. In addition to their function as Hox‐cofactors, TALE homeoproteins control multiple crucial developmental processes through Hox‐independent mechanisms. Here, we will review recent findings on the function of both Hox and TALE proteins in cell differentiation, referring mostly to vertebrate species. In addition, we will discuss the direct implications of this knowledge on cell plasticity and cell reprogramming. Developmental Dynamics 243:76–87, 2014. © 2013 Wiley Periodicals, Inc.