Palmoplantar Keratodermas (PPKs) are a heterogeneous group of skin disorders whose common feature is thickening of the epidermis in the palms of the hands and soles of the feet. Individuals with PPKs report varying degrees of palmoplantar pain that can severely affect quality of life. Due in part to the rarity of these conditions, PPK-associated pain remains poorly understood and inadequately treated. The heterogeneity of pain prevalence and presentations across the many forms of PPK suggests that there may exist corresponding heterogeneity in the cellular and molecular mechanisms that drive and shape PPK-associated pain. In this review we discuss candidate mechanisms for this pain, including alterations in skin architecture, involvement of multiple cell types, and neuropathic changes to the sensory nervous system. Greater understanding of these mechanisms might provide a rational basis for the development of improved approaches to prevention and treatment of pain in individuals with PPK 1).