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An optical biosensor utilizing long-range surface plasmon-polariton waveguides is discussed. This paper first reviews the technology and its various applications such as protein sensing, cell detection, and disease diagnostics, and then presents results on the detection of small molecules using the biosensor. The surface was functionalized with 16-mercaptohexadecanoic acid and activated using carbodiimide chemistry. Covalent attachment of N-hydroxysulfosuccinimide ester (Sulfo-NHS) of molecular weight ~200 Da produced a significant response with a signal-to-noise ratio of ~81 as a result of molecular monolayer formation. Since carbodiimide chemistry is a protein coupling approach commonly used to functionalize biosensors, a calibration scheme for extracting the actual amount of attached protein based on biosensor responses to NHS is proposed.