A thorough knowledge of the cellular and molecular basis of the structure and function of peripheral nerves is of paramount importance not only for a better understanding of the fascinating biology of the peripheral nervous system but also for providing critical insights into the various diseases affecting peripheral nerves as the firm foundation of potential treatments. Genetic approaches in model organisms, in combination with research on hereditary forms of neuropathies, have contributed significantly to our progress in this field. In this review, we will focus on recent advances using these synergistic approaches that led to the identification of small Rho GTPases and their regulators as crucial functional players in proper development and function of myelinated peripheral nerves, with a particular emphasis on the cell biology of Schwann cells in health and disease.