The remote but heart-encircling location of pericardial fluid confers this biofluid unique properties. Once past the limitation of the invasive collection, for instance, on occasion of heart surgery or pericardiocentesis, the scrutiny of pericardial fluid content can be of great interest in cardiovascular research. This liquid concentrates many heart-derived factors, thus enclosing several surrogate markers for the diagnosis or prognosis of a large spectrum of diseases either pericardial (e.g. malignant or tuberculous pericarditis) or non-pericardial/heart diseases (e.g. coronary artery disease or valvular heart diseases). Herein, for the first time, the molecular knowledge of pericardial fluid is reviewed, through an in-depth literature search and mining, and then translated into a network map of the diseases influencing pericardial fluid composition. The suitability of pericardial fluid for biomarker research could be demonstrated by evident molecular profiles between different conditions as well as by stronger correlations to cardiac structural and functional parameters, fainter or lacking in plasma/serum. Also highlighted here are the results of mechanistic research conducted with pericardial fluid in several hot topics of research, such as chronotropy, inotropy, coronary perfusion and cardiac electrophysiology. Moreover, the progress in intrapericardial therapeutics, motivated by pericardial fluid’s low clearance rates, higher efficiency and lesser risk of systemic effects over conventional delivery methods, is surveyed and discussed.