Ultrasensitive detection methods for nicotine and its major metabolite, cotinine, are needed in order to provide reliable data that can help study environmental tobacco smoke and their effects on non-smokers especially children. Some of the studies on passive smoke have confirmed that the exposure of smoke jeopardizes children's health even prior to their birth and is a primary cause for many abnormalities. To assess and understand the correlations of smoke exposure to smoke-related diseases, researchers have used nicotine and cotinine as the principle biomarkers. However, there is a lack of a sensitive analytical method that can monitor trace levels of nicotine in second hand smoke and third hand smoke in a compact portable detector design with minimal sample preparation and quick analysis time. Reliable and sensitive detection of nicotine is essential to track and understand numerous health and psychological effects caused by passive smoke. We demonstrate laser wave mixing, as a highly sensitive nonlinear spectroscopic method that is suitable for field use for a wide range of environmental and biomedical applications. Wave mixing only requires a small amount of sample (nanogram). Hence, it can be conveniently interfaced to microarrays, microfluidics, chip-based capillary electrophoresis, and other flow systems to yield excellent chemical specificity and detection sensitivity levels (pico- or femto-mole). Two of the major factors that allow wave-mixing signals to yield high signal-to-noise ratio are cubic dependence on laser power and square dependence on analyte concentration. Thus far, the results indicate that nicotine and cotinine can be detected and separated in their native form label-free using an ultraviolet laser as well as their complexes obtained by a two-reagent reaction. Current results show the detection limit of 2.7 ng /mL for nicotine (2.3 x 10⁻¹⁸ mol) and 544 ng /mL for cotinine (6.0 x 10⁻¹⁷ mol) complexes using a visible laser. The detection limit has a great chance to meet the requirement for real world applications. The method could potentially allow reliable real-time detection of nicotine in indoor environments to accurately monitor smoke exposure to children. Moreover, measurement of cotinine in biological fluids would assist in understanding smoke-related diseases.