Comorbidities between mental and physical disorders are frequently encountered during development. The association is especially evident in the first years of life, when genetically determined syndromes can manifest with multisystemic abnormalities, including both medical and psychiatric disturbances. Paradigmatic is the case of the 22q11.2 deletion syndrome, in which cardiac, skeletal, and immunological abnormalities are associated with a higher risk of intellectual disability, autism, and schizophrenia. This chapter selectively reviews common comorbidities in children and adolescents, underscoring the bidirectionality of the relationship, so that medical diseases can induce psychiatric symptoms and psychiatric disorders can have prominent physical symptoms. Of particular clinical relevance are the psychiatric manifestations of specific medical conditions, such as psychosis from anti-NMDA receptor autoimmune encephalitis, steroid-induced mania, iron-deficiency hyperactivity, and depression from hypothyroidism. In these cases, treatment of the underlying physical dysfunction can bring resolution or significant improvement of the mental condition. Possible psychiatric sequelae of symptomatic SARS-CoV-2 have been reported in children as part of a long COVID syndrome. Anxiety and mood disorders are common during development, often manifesting with physical symptoms. Chronic medical diseases and, in general, prolonged hospitalization can induce anxiety and depression so that prevention of mental disorders in medically ill children has considerable clinical relevance.