.SignificanceSkin is the largest organ and also the first barrier of body. Skin diseases are common, and cutaneous microcirculation is relative to various diseases. Researchers attempt to develop novel imaging techniques to obtain the complex structure, components, and functions of skin. Modern optical techniques provide a powerful tool with non-invasiveness, but the imaging performance suffers from the turbid character of skin. In vivo skin optical clearing technique has been proposed to reduce tissue scattering and enhance penetration depth of light and became a hot topic of research.AimThe aim of this review is to provide a comprehensive overview of recent development of in vivo skin optical clearing methods, how in vivo skin optical clearing enhances imaging performance, and its applications in study and light therapy of various diseases.ApproachBased on the references published over the last decade, the important milestones on the mechanism, methods, and its fundamental and clinical applications of in vivo skin optical clearing technique are provided.ResultsWith the deepening understanding of skin optical clearing mechanisms, efficient in vivo skin optical clearing methods were constantly screened out. These methods have been combined with various optical imaging techniques to improve imaging performances and acquire deeper and finer skin-related information. In addition, in vivo skin optical clearing technique has been widely applied in assisting study of diseases as well as achieving safe, high-efficiency light-induced therapy.ConclusionsIn the last decade, in vivo skin optical clearing technique has developed rapidly and played an important role in skin-related studies.