The etiology of pericardial effusions remains unresolved in many cases because not the full spectrum of diagnostic methods including cytology, histology, immunohistology and PCR on cardiotropic agents, which are currently available, used in many institutions. After comprehensive clinical workup and use of imaging methods, such as echocardiography and cardiac MRI, pericardiocentesis and epicardial and pericardial biopsy were carried out under pericardioscopical control of the biopsy site. Biopsies and fluid were evaluated by cytological, histological, immunological and molecular (PCR) methods in 259 patients of our tertiary referral center following an identical clinical pathway, diagnostic and therapeutic algorithm in all cases. A standard clinical pathway and the same diagnostic and therapeutic algorithms were used in all cases. When all methods are applied to patients with pericardial effusions, “idiopathic” pericardial effusion is no longer a relevant diagnosis. Autoreactive and lymphocytic pericardial effusions are the leading diagnosis in 35 % of patients in the prospective Marburg registry, followed by malignant effusions in 28 % of cases. Viral genome was assessed in fluid and epi- as well as pericardial biopsies in 12 %, followed by post-traumatic/iatrogenic effusions in 15 % and purulent/bacterial effusions in only 2 %. Pericardioscopy permits the macroscopic inspection of the pulsating heart and its disease-associated macroscopic alterations. It also permits safe and targeted biopsy for further investigations of the tissue. Therapy, tailored to the individual etiology, can be selected such as intrapericardial instillation in autoreactive effusions with triamcinolone and with cisplatin or thiotepa in neoplastic effusions. With this approach the recurrence of pericardial effusion can be avoided effectively. A comprehensive approach to the diagnosis of pericardial effusions in conjunction with pericardioscopy for targeted tissue sampling is the prerequisite for an etiologically based intrapericardial and systemic treatment, which improves outcome and prognosis.