Breath analysis research is being successfully pursued using a variety of analytical methods, prominent amongst which are gas chromatography with mass spectrometry, GC-MS, ion mobility spectrometry, IMS, and the fast flow and flow-drift tube techniques called selected ion flow tube mass spectrometry, SIFT-MS, and proton transfer reaction mass spectrometry, PTR-MS. In this paper the case is made for real-time breath analysis by obviating sample collection into bags or onto traps that can suffer from partial degradation of breath metabolites or the introduction of impurities. Real-time analysis of a broad range of volatile chemical compounds can be best achieved using SIFT-MS and PTR-MS, which are sufficiently sensitive and rapid to allow the simultaneous analyses of several trace gas metabolites in single breath exhalations. The basic principles and the ion chemistry that underpin these two analytical techniques are briefly described and the differences between them, including their respective strengths and weaknesses, are revealed, especially with reference to the analysis of the complex matrix that is exhaled breath. A recent innovation is described that combines time-of-flight mass spectrometry with the proton transfer flow-drift tube reactor, PTR-TOFMS, which provides greater resolution in the analytical mass spectrometer and allows separation of protonated isobaric molecules. Examples are presented of some recent data that well illustrate the quality and real-time feature of SIFT-MS and PTR-MS for the analysis of exhaled breath for physiological/biochemical/pharmacokinetics studies and for the identification and quantification of biomarkers relating to specific disease states.