Comorbidity has become an increasingly popular theme in psychiatry and clinical psychology, although its heuristic value was recognised long ago. Frequently used in research and practice, no definition of comorbidity is uniformly accepted and it has no comprehensive and coherent theoretical framework. These factors have led to substantial variation in the magnitude of comorbidity across studies. The variability in the definition, assessment and design of comorbidity studies has led to an increasingly complex and confusing picture about the potential value of this concept. The full exploration of mechanisms of comorbidity requires an interdisciplinary approach to investigating nosology, assessment, and underlying models of comorbidity, as well as experimental study designs beyond the scope of clinical and epidemiological studies. A more precise specification of comorbidity patterns might help identify common biochemical and cognitive markers relevant in the aetiology of specific mental disorders as well as comorbid conditions. Critical issues that might help us understand and explain the variability of findings are described.