Solar irradiation consists of light at ultraviolet (UV), visible, and infrared spectrum. Since ancient time, sun exposure has been used for treating various diseases. Currently, phototherapy is an essential part of dermatology practice for treating various skin conditions including for regenerative purposes. The proposed mechanisms responsible for phototherapy, particular those in the UV region, mostly focus on immune suppressive effects of lights. Little is known regarding the mechanisms involved in visible light therapy. It is recognized that specific absorption of photon energy by chromophore, or photoacceptor, is responsible for light and tissue interaction. Although non-thermal, low energy visible light has been used to promote wound healing and rejuvenate photodamaged skin clinically, the molecular mechanisms involved remained unclear. In 2003, we proposed and demonstrated that low-energy laser (Helium-Neon laser) emitting visible light at 632.8 nm induces vitiligo repigmentation. Subsequently, we demonstrated that He-Ne laser has multifaceted biological effects on keratinocytes and melanoblast that create a favorable environment for vitiligo repigmentation. More recently, we showed that Helium-Neon laser significantly increases the mitochondrial DNA copy number, induces the expression of regulatory genes for mitochondrial biogenesis, and upregulated the antioxidant enzyme expression of primitive melanoblasts. Mechanistically, we demonstrated that Helium-Neon laser initiated mitochondrial retrograde signaling via a Ca2+-dependent cascade. In summary, visible light phototherapy induces vitiligo repigmentation via mitochondrial retrograde signaling. Combination of visible light with other spectrum of light may have important clinical applications in the other aspects of regenerative medicine including wound healing and skin rejuvenation.