Skin retains numerous low-molecular-weight compounds (metabolites). Some of these compounds fulfill specific physiological roles, while others are by-products of metabolism. The skin surface can be sampled to detect and quantify skin metabolites related to diseases. Miniature probes have been developed to detect selected high-abundance metabolites secreted with sweat. To characterize a broad spectrum of skin metabolites, specimens are collected with one of several available methods, and the processed specimens are analyzed by chromatography, mass spectrometry (MS), or other techniques. Diseases for which skin-related biomarkers have been found include cystic fibrosis (CF), psoriasis, Parkinson's disease (PD), and lung cancer. To increase the clinical significance of skin metabolomics, it is desirable to verify correlations between metabolite levels in skin and other biological tissues/matrices.