Introduction: Obsessive-compulsive disorder (OCD) is clearly a heterogeneous syndrome in which comorbidity is the rule rather than the exception and is often 'phase-specific'. Comorbid conditions have a negative impact on OCD outcome and may clearly impact the disease trajectory. Nevertheless, in the current literature there is an impressive neglect of comorbidities in clinical trials and treatment approaches for these conditions are still not evidence-based. Areas covered: In this paper we summarized the available data on the treatment of the main OCD comorbidities (mood and anxiety disorders, 'bipolar neurosis', tics and OCD-related disorders, addictions and impulsive disorders, eating disorders, attention deficit hyperactivity disorder, psychoses, and post-infective syndromes). Expert opinion: To achieve the goals of 'precision medicine' there is a critical need for deconstructing current diagnostic groups with biomarkers to predict and improve response to treatment. Despite the continuous efforts of several researchers in subtyping homogeneous samples of OCD patients (for example the comorbidity-based subclassification), current available treatments are still syndrome-based rather than network dysfunctions-based. Identifying the homogenous subgroup, subtyping patients according to comorbidity patterns, symptom dimensions, clinical course, neurocognitive and neurophysiological dysfunctions, could represent an essential first step in the direction of a 'precision medicine' approach.