The duration of untreated illness (DUI), defined as the interval between the onset of a psychiatric disorder and the administration of the first pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions including schizophrenia and psychotic disorders (duration of untreated psychosis), and mood and anxiety disorders. Converging evidence indicates that a prolonged DUI may be viewed as a negative prognostic factor in schizophrenia and increasing data point toward a similar conclusion in mood and anxiety disorders. Through a Medline search, the present article highlights the role of the DUI in this group of psychiatric disorders, focusing on social and psychopathological determinants of the DUI, as well as the clinical consequences related to a longer DUI in terms of outcome. Hypotheses on neurobiological mechanisms underpinning outcome differences in relation to a prolonged DUI are provided and methodological limitations related to the assessment of the DUI in published studies and clinical practice discussed. Finally, given that DUI is supposed to be a potentially modifiable prognostic factor, intervention programs aimed to reduce this variable are briefly considered and discussed.