AbstractThe development of selected ion flow tube mass spectrometry, SIFT‐MS, is described from its inception as the modified very large SIFT instruments used to demonstrate the feasibility of SIFT‐MS as an analytical technique, towards the smaller but bulky transportable instruments and finally to the current smallest Profile 3 instruments that have been located in various places, including hospitals and schools to obtain on‐line breath analyses. The essential physics and engineering principles are discussed, which must be appreciated to design and construct a SIFT‐MS instrument. The versatility and sensitivity of the Profile 3 instrument is illustrated by typical mass spectra obtained using the three precursor ions H3O+, NO+ and ${\rm O}_{{\rm 2}}^{{\rm + } \cdot }$, and the need to account for differential ionic diffusion and mass discrimination in the analytical algorithms is emphasized to obtain accurate trace gas analyses. The performance of the Profile 3 instrument is illustrated by the results of several pilot studies, including (i) on‐line real time quantification of several breath metabolites for cohorts of healthy adults and children, which have provided representative concentration/population distributions, and the comparative analyses of breath exhaled via the mouth and nose that identify systemic and orally‐generated compounds, (ii) the enhancement of breath metabolites by drug ingestion, (iii) the identification of HCN as a marker of Pseudomonas colonization of the airways and (iv) emission of volatile compounds from urine, especially ketone bodies, and from skin. Some very recent developments are discussed, including the quantification of carbon dioxide in breath and the combination of SIFT‐MS with GC and ATD, and their significance. Finally, prospects for future SIFT‐MS developments are alluded to. © 2010 Wiley Periodicals, Inc., Mass Spec Rev 30:236–267, 2011