Measurement of skin blood flow is a sensitive marker of C-fiber neurovascular dysfunction. It precedes development of abnormalities in diabetes mellitus, correlates with in vivo indices of the metabolic syndrome, and may be a "benchmark" for future studies on agents to improve microvascular dysfunction in diabetes mellitus. Skin blood flow can be measured under basal and stimulated conditions. There are different methods of evaluation. Iontophoresis and microdialysis are novel methods of drug delivery and the latter may be used as a means of extracting analytes in the skin. Theses methods are not invasive (iontophoresis) or minimally invasive (microdialysis). They can be performed repeatedly and safely in most patients. The use of microdialysis may be limited by sampling only water-soluble molecules. An alternative to microdialysis is iontophoresis, which works better with polar molecules. A combination of microdialysis and iontophoresis techniques can be useful in assessment of the pharmacokinetics of polar and nonpolar agents and the physiology and pathophysiology of the skin neurovascular system.