Drug-membrane interactions play a crucial rote in the pharmacology and activity of drugs. The measurement of drug association to lipid membranes has conventionally been measured by fluorescence and other spectroscopic methods. However, a main disadvantage of fluorescence labeling of drugs is that the introduction of ftuorophores may change the molecules physical properties, such as charge, hydrophobic or hydrophitic character, and structure. To circumvent these problems, Ultraviolet-Visible Sum Frequency Generation (UV-Vis SFG) has been developed as an uttrasensitive and label-free technique to detect small-molecule drug association to lipid membranes. Four different classes of drugs, a nonsteroidat anti-inflammatory drug (ibuprofen), antibiotic (azithromycin), antifungat (tolnaftate), and local anesthetic (tetracaine), were examined. Drug association was measured on planar supported lipid bilayers (PSLBs) of 1,2-dioleoyi-sn-gtycero-3-phophocholine (DOPC). Equilibrium association constants of the drugs were obtained and correlate well to the partition coefficients of the drugs in a liposome membrane-water system. UV-Vis SFG is a powerful and novel technique to directly measure the association of drugs to a single biological membrane without chemical modification.