Background: Visible light is absorbed by photoacceptors in pigmented and non-pigmented mammalian cells, activating signaling cascades and downstream mechanisms that lead to the modulation of cellular processes. Most studies have investigated the molecular mechanisms and therapeutic applications of UV and the red to near infrared regions of the visible spectrum. Considerably less effort has been dedicated to the blue, UV-free part of the spectrum. Objective: In this review, we discuss the current advances in the understanding of the molecular photoacceptors, signaling mechanisms, and corresponding therapeutic opportunities of blue light photoreception in non-visual mammalian cells in the context of inflammatory skin conditions. Methods: The literature was scanned for peer-reviewed articles focusing on the molecular mechanisms, cellular effects, and therapeutic applications of blue light. Results: At a molecular level, blue light is absorbed by flavins, porphyrins, nitrosated proteins, and opsins; inducing the generation of ROS, nitric oxide release, and the activation of G protein coupled signaling. Limited and contrasting results have been reported on the cellular effects of blue light induced signaling. Some investigations describe a regulation of proliferation and differentiation or a modulation of inflammatory parameters; others show growth inhibition and apoptosis. Regardless of the elusive underlying mechanism, clinical studies show that blue light is beneficial in the treatment of inflammatory skin conditions. Conclusion: To strengthen the use of blue light for therapeutic purposes, further in depth studies are clearly needed with regard to its underlying molecular and cellular mechanisms, and their translation into clinical applications.