Comorbidity is widely used in psychiatry, although few studies have considered the conceptual and methodological problems deriving from the transposition of this term from medicine to psychiatry. Comorbidity should be defined as two or more diseases, with distinct aetiopathogenesis (or, if the aetiology is unknown, with distinct pathophysiology of organ or system), that are present in the same individual in a defined period of time. In psychiatry, comorbidity is often an artefact for several reasons: (a) different assessment methods; (b) improper utilisation of the term comorbidity to indicate the association of symptoms instead of diseases; (c) number and characteristics of hierarchical exclusion rules used in classification systems; (d) nosologic classification in disorders (a generic term) instead of syndromes (a more precise concept, that allows clinicians to consider the hierarchy and the qualitative specificity of symptoms); (e) excessive splitting of classical syndromes into small disorders with inappropriate and overlapping boundaries; (f) too frequent revision of the diagnostic criteria, that changes diagnostic threshold; (g) number of clinical entities considered. Biological and psychological hypotheses that investigate the complexity of comorbidity findings are here presented; it is underlined that comorbidity should be the epidemiological descriptive starting point to build hypotheses that must be clear and rigorously defined, with specified usefulness and limits. Finally, the hypotheses should be tested with specific methodologies.