Peripheral markers of psychiatric illness provide a potentially important window into the pathophysiology of a number of psychiatric illnesses. Direct access to pathophysiological processes is fraught with difficulty. However, receptor-regulated second messenger-mediated calcium shifts are an accessible and practical method by which to examine changes in a clinical population. This is possible because platelets and neurons share some physiological features. The platelet intracellular calcium response to receptor stimulation has previously been used as a peripheral marker of psychiatric illness across a range of neurotransmitters, including serotonin, dopamine and glutamate. This review considers the specificity and selectivity of this response and its use in psychotic and mood disorders.