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Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown pathogenesis, characterised by fatigue which is not relieved by rest, accompanied by assorted symptoms including cognitive difficulties, pain, and unrefreshing sleep. One hallmark of the symptom complex in CFS is a transient exacerbation of the fatigue state after relatively minor physical activity or cognitive activity often termed a post-exertional exacerbation . By applying challenge paradigms, the studies presented in this thesis aimed to analyse the biological underpinnings of the disorder during periods of worsened fatigue and symptoms following the imposition of environmental challenges a physical exercise protocol and a simulated-driving protocol (representing a cognitively-demanding task). These paradigms allowed analysis of a working conceptual model that CFS is a result of central sensitisation , representing augmented responsiveness of the central nervous system (CNS) to signals either from the periphery or from within the brain - resulting in altered sensory processing within the brain and ultimately the excessive conscious sensation of fatigue. Across the two challenge studies, patients with CFS reported high levels of fatigue in their baseline state (consistent with the diagnostic criteria for the disorder). This was measured using a new fatigue scale specifically designed for these studies to allow real-time measurement of the phenomenon. In comparison to matched healthy participants, at baseline, the patients had impairments in cognitive function, longer night-time sleep, less day-time physical activity and movement, and less heart rate variability - an index of vagal activity, around the time of night-time sleep, but no alterations in gene expression for biomarkers previously linked with the sensation of fatigue, or in indices of interoception. These findings are generally consistent with previous evidence for autonomic nervous system and cognitive disturbances in patients with CFS. However, while both the physical and cognitive challenges induced an exacerbation of fatigue lasting hours-to-days in patients with CFS (with little or no change in healthy participants), there were no corresponding changes in gene expression, cognitive performance, indices of interoception, indices of vagal activity, or sleep and activity patterns. As such, the inability to detect meaningful changes in biological parameters indirectly reflecting central sensitisation post-challenge did not allow for confirmation or denial of the hypothesis that the post-exertional exacerbation of fatigue and related symptoms is due to central sensitisation . Further studies are warranted using these challenge protocols in conjunction with more direct measures of central sensitisation such as functional neuro-imaging.