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Exhaled breath contains more than 1000 constituents at trace level concentrations, with a wide variety of these compounds potentially serving as biomarkers for specific diseases, physiologic status, or therapeutic progress. Some of the compounds in exhaled breath (EB) are well studied, and their relationship with disease pathologies is well established. However, molecularly specific analysis of such biomarkers in EB at clinically relevant levels remains an analytical and practical challenge due to the low levels of such biomarkers frequently below the ppb (v/v) range in EB. In this contribution, mid-infrared (MIR) spectroscopic sensing techniques are reviewed for potential application in breath diagnostics. While the spectral regime from 3-20 Â¿m has already been utilized for fundamental studies on breath analysis, significant further improvements are in demand for substantiating MIR spectroscopy and sensing techniques as a suitable candidate for clinically deployable breath analyzers. Several advantageous features including inherent molecular selectivity, real-time monitoring capability, comparable ease of operation, potentially low costs, and a compact device footprint promise reliable optical diagnostics in the MIR. Hence, while the application of MIR spectroscopy and sensing systems to breath analysis yet appear in their infancy, recent progress on advanced MIR light sources, waveguides, and device concepts forecasts next-generation optical sensing platforms suitable for addressing the challenges of in situ breath diagnostics.