Phototherapy is an efficient treatment for many cutaneous diseases that involve the activation of inflammatory pathways or the overgrowth of cells with aberrant phenotype. In this review, we discuss recent advances in photoimmunology, focusing on the effects of UV-based therapies currently used in dermatology. We describe the molecular responses to the main forms of photo(chemo)therapy such as UVB, UVA-1, and PUVA that include the triggering of apoptotic or immunosuppressive pathways and help to clear diseased skin. The early molecular response to UV involves DNA photoproducts, the isomerization of urocanic acid, the secretion of biophospholipids such as platelet activating factor (PAF), the activation of aryl hydrocarbon receptor and inflammasome, and vitamin D synthesis. The simultaneous and complex interaction of these events regulates the activity of the immune system both locally and systemically, resulting in apoptosis of neoplastic and/or benign cells, reduction of cellular infiltrate, and regulation of cytokines and chemokines. Regulatory T-cells and Langerhans cells, among other skin-resident cellular populations, are deeply affected by UV exposure and are therefore important players in the mechanisms of immunomodulation and the therapeutic value of UV in all its forms. We weigh the contribution of these cells to the therapeutic application of UV and how they may participate in transferring the direct impact of UV on the skin into local and systemic immunomodulation. Moreover, we review the therapeutic mechanisms revealed by clinical and laboratory animal investigations in the most common cutaneous diseases treated with phototherapy such as psoriasis, atopic dermatitis, vitiligo, and cutaneous T-cell lymphoma. Better understanding of phototherapeutic mechanisms in these diseases will help advance treatment in general and make future therapeutic strategies more precise, targeted, personalized, safe, and efficient.