Psoriasis is a chronic inflammatory, immune-mediated skin disease affecting 2 to 3% of the general population and may cause significant quality-of-life impairment. Psoriasis and psoriatic arthritis are associated with increased atherothrombotic diseases, including myocardial infarction, deep venous thrombosis, and reduced life span. Both disease-specific and non-disease-specific risk factors are likely to fuel one another in deleterious vicious circles. Disease-specific risk factors are those that are a direct consequence of psoriasis inflammation and include hyperhomocysteinemia, elevated C-reactive protein, elevated blood inflammatory cytokines, and platelet hyperactivity. Non-disease-specific risk factors include insulin resistance/diabetes, obesity, dyslipidemia, hypertension, metabolic syndrome, and habitual tobacco smoking. The presence of cardio-metabolic comorbidities has also relevant implication in the therapy and global approach to patients with psoriasis. Traditional systemic antipsoriatic agents frequently negatively affect cardio-metabolic comorbidities and may have important interactions with drugs commonly used by psoriasis patients. Thus, patients with psoriasis should be treated effectively and encouraged to aggressively correct their modifiable cardiovascular risk factors.