Plant epidermal cells are the outermost cells that directly interact with ambient conditions. According to their functional roles, epidermal cells differentiate into a variety of specialized cell structures, which participate in activities such as plant defense, evaporation reduction, pollinator attraction, seed dispersal, and the synthesis and storage of se-condary metabolites. MIXTA/MIXTA-like genes have been identified as key regulators of epidermal cell differentiation in many plants. These genes may function in different tissues (e.g., petals, leaves, ovules and ovaries) in different plants by regulating the differentiation of epidermal cells. They also play essential roles in trichome formation, cuticle biosynthesis, conical epidermal cell differentiation, and in initializing seed hair development. Among which, trichome development is a hot research topic because of its functional role. For instance, leaf indumentum is deemed as an important morphological feature in the defense against phytophagous insects, and seed hairs dispersed from poplars, willows and chinars are all differentiated from epidermal cells during seed maturation; whereas artemisinin is synthesized and stored in the glandular hairs of Artemisia annua. Here, we review and summarize the characteristics of MIXTA/MIXTA-like genes, as well as their biological functions in regulating epidermal cell differentiation. This paper provides essential information for facilitating studies on the molecular mechanisms underlying epidermal cell differentiation and for accelerating the breeding program of traits related to epidermal cell differentiation.