This chapter focuses on the adverse effects of retinoids on central and peripheral nervous system and muscles. Retinoids are either natural or synthetic compounds with functional properties of vitamin A. Retinoids are known to exert pleiotropic effects on the development, differentiation, and metabolism of skeletal muscle cells, with a possible mechanism through the induction of oxidative stress. Vitamin A is fat-soluble, adipose tissue actively involved in retinoid homeostasis. Diplopia and strabismus have been reported in several patients taking retinoids, including acitretin. Myalgias, muscle tenderness, and stiffness may be associated with the use of retinoids. Severe and potentially life-threatening adverse effect on muscles, namely acute rhabdomyolysis, has been reported with use of oral isotretinoin. Prospective and retrospective studies demonstrated neurotoxicity of isotretinoin and acitretin on peripheral nerves. Neurophysiologic evaluations of the patients were consistent with distal sensory neuropathy, mainly with axonal features.