The cause of acute and recurrent pericarditis is often a major concern for the clinicians in clinical practice. Several possible causes of pericarditis can be listed, as the pericardium may be involved in a large number of systemic disorders or may be diseased, as an isolated process. The reported diagnostic yield of extensive laboratory evaluation and pericardiocentesis is low in the absence of cardiac tamponade or suspected neoplastic, tuberculous, and purulent pericarditis. Patients with pericarditis can be safely managed on an outpatient basis without a thorough diagnostic evaluation unless a specific cause is suspected or the patient has high-risk features, or both. A targeted aetiological search should be directed to the most common cause on the basis of the clinical background, epidemiological issues or specific presentations. In developed countries the clinicians should rule out neoplastic, tuberculous, and purulent pericarditis, as well as pericarditis related to a systemic disease.