The pericardium is a double-layered fibro-serous sac that envelops the majority of the surface of the heart as well as the great vessels. Pericardial fluid is also contained within the pericardial space. Together, the pericardium and pericardial fluid contribute to a homeostatic environment that facilitates normal cardiac function. Different diseases and procedural interventions may disrupt this homeostatic space causing an imbalance in the composition of immune mediators or by mechanical stress. Inflammatory cells, cytokines, and chemokines are present in the pericardial space. How these specific mediators contribute to different diseases is the subject of debate and research. With the advent of highly specialized assays that can identify and quantify various mediators we can potentially establish specific and sensitive biomarkers that can be used to differentiate pathologies, and aid clinicians in improving clinical outcomes for patients.