The functional ingredients for skin-related products have been highly recognized accompanied by the consumers’ curiosity and instrumental improvement. The targeted location of a functional active ingredient in the skin organelle could be very critical information for its product development, safety evaluation, and benefit claims. Due to those factors, mass spectrometry technology exhibited rapid growth in those research areas because it can accurately and sensitively determine the ingredient molecular weights and locations. In this min review, a summarized figure was created for mass spectrometry technology applications in skin research in the last two decades or so. Compared to other related technologies, the uniqueness and advantage of chromatographic-mass spectrometry and mass spectrometry imaging were also emphasized. Several typical examples from separation, isotopic labeling, and combination with Franz cell were discussed.