Stress in mammals triggers a neuroendocrine response mediated by the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Increased activity of these two systems induces behavioural, cardiovascular, endocrine and metabolic cascades that enable the individual to fight or flee and cope with the stress. Our understanding of stress and stress-response mechanisms is generally robust. Here, however, we review three themes that remain controversial and perhaps deserve further scrutiny and investigation before they achieve canonical status. The themes are, first, hypocortisolaemia in post-traumatic stress disorder (PTSD). A reduction rather than a stress-induced increase in adrenal glucocorticoid levels, as seen in major depressive disorder (MDD), is puzzling and furthermore is not a consistent feature of PTSD. Overall, studies on PTSD show that glucocorticoid levels may be normal or higher or lower than normal. The second theme concerns the reduction in volume of the hippocampus in MDD attributed to the neurotoxicity of hypercortisolaemia. Again, as for hypocortisolaemia in PTSD, reduced hippocampal volume in MDD has been found in some but not all studies. Third, the discovery of a causal association between Helicobacter pylori and peptic ulcers apparently brought to an end the long-held view that peptic ulceration was caused predominantly by stress. However, recent studies suggest that stress can cause peptic ulceration in the absence of H. pylori. Predictably, the aetiological pendulum of gastric and duodenal ulceration has swung from 'all stress' to 'all bacteria' followed by a sober realisation that both factors may play a role. This raises the question as to whether stress and H. pylori interact, and if so how? All three controversies are of clinical significance, pose fundamental questions about stress mechanisms and offer important areas for future research.