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Breath is a mixture of nitrogen, oxygen, carbon dioxide, water vapour, inert gases, and a small fraction of trace volatile organic compounds (VOCs) in the parts per million by volume to parts per trillion by volume range. VOCs can be produced anywhere in the body as a result of physiological and pathophysiological processes, and are transported via the bloodstream to the lungs where they are exhaled in breath. On the basis that VOCs in breath are representative of VOCs in the blood and therefore biochemical processes occurring in the body, the analysis of exhaled breath may become a noninvasive tool for use in clinical practice. This thesis documents the development of the analytical technique of chemical ionisation reaction time-of-flight mass spectrometry (CIR-TOF-MS) for the analysis of VOCs in exhaled breath, exploring the challenges associated with breath sampling to its application in clinical studies. Initial work focused on the design of a suitable breath sampling device that coupled directly to the CIR-TOF-MS instrument to allow the on-line, real-time analysis of breath. The analysis of exhaled breath from healthy individuals allowed a common group of breath VOCs to be identified and quantified. The CIR-TOF-MS system was applied to a number of clinical trials examining the breath of individuals with cystic fibrosis (9 cystic fibrosis children, 4 healthy children), asthma (35 asthmatic subjects, 5 COPD, 28 healthy controls) and cancer (4 female cancer subjects, 10 healthy female controls), for which the latter study required the investigation of off-line breath collection. The analysis of VOCs emitted from bacterial and fungal cultures in vitro was also explored, as a means to support the hypothesis that the measurement of VOCs in exhaled breath could be used to identify infection status in vivo. Within these applications, CIR-TOF-MS was able to demonstrate that the chemical profile of breath has the potential to identify the presence of infection or disease.