Continuous integration of signals from the micro- and macro-environment is necessary for somatic stem cells to adapt to changing conditions, maintain tissue homeostasis, and activate repair mechanisms. G-protein coupled receptors (GPCRs) facilitate this integration by binding to numerous hormones, metabolites, and inflammatory mediators, influencing a diverse network of pathways that regulate stem cell fate. This adaptive mechanism is particularly relevant for tissues that are exposed to environmental assault, like skin. The skin is maintained by a set of basal keratinocyte stem and progenitor cells located in the hair follicle and interfollicular epidermis, and several GPCRs and their signaling partners serve as makers and regulators of epidermal stem cell activity. GPCRs utilize heterotrimeric G protein dependent and independent pathways to translate extracellular signals into intracellular molecular cascades that dictate the activation of keratinocyte proliferative and differentiation networks, including Hedgehog GLI, Hippo YAP1 and WNT/β-catenin, ultimately regulating stem cell identity. Dysregulation of GPCR signaling underlines numerous skin inflammatory diseases and cancer, with smoothened-driven basal cell carcinoma being a main example of a GPCR-associated cancer. In this review, we discuss the impact of GPCRs and their signaling partners in skin keratinocyte biology, particularly in the regulation of the epidermal stem cell compartment.