Acne in Apert syndrome and unilateral segmental acneiform nevus are associated with mutations of fibroblast growth factor receptor 2 (FGFR2), which are likely to be involved in the pathogenesis of acne. Translational animal and cellular models, developmental biology studies and clinical observations have contributed to our understanding of FGF-FGFR2 signaling in the pilosebaceous follicle. The importance of FGF-FGFR2 signaling in mesenchymal-epithelial interaction for skin appendage formation, pilosebaceous follicle homeostasis, comedogenesis and sebaceous gland proliferation is explored. Overstimulation of FGFR2 signaling with increased expression of interleukin-1alpha explains acne in Apert syndrome und nevus comedonicus. Androgen-mediated up-regulation of FGFR2 signaling could be the initiating signal in the pathogenesis of acne. The gain of function FGFR2 mutations in Apert syndrome and unilateral acneiform nevus are most helpful model diseases for uncovering the fundamental process of androgen-dependent mesenchymal-epithelial FGF-FGFR2 signaling in acne in Apert syndrome, nevus comedonicus and acne vulgaris.