Optical spectroscopy can be used for trace-level gas analysis in different applications, including exhaled breath research. A common approach is the targeted on-line, real-time analysis of small molecules (two to five atoms). Currently, the methodology is normally used for the detection of single analytes at trace levels, or two to three species at most at the same time. The main limitation preventing sensitive multi-species detection has been the limited fast scanning range of the lasers used as light sources. This limitation is currently being eliminated by the availability of optical frequency combs (OFC) which offer wide spectral bandwidths and the benefits of a laser-type light source. Recent advances in mid-infrared OFC technology allow measurements in the so-called molecular fingerprint region of the electromagnetic spectrum, where many molecules have strong fundamental vibrational transitions that enable sensitive detection. Several technical hurdles remain to be overcome, but if these problems can be solved laser absorption spectroscopy has the potential to challenge mass spectrometry in on-line multi-species trace gas analysis.