The pericardial space provides a homeostatic environment that facilitates optimal cardiac function. The pericardial space contains pericardial fluid (PCF) and other tissue sources, including pericardial adipose tissue and the great vessels. Given its proximity to the heart, PCF has emerged as a potential diagnostic, prognostic, and therapeutic vehicle. As such, the biochemical and humoral characteristics of PCF have recently been the focus of several studies. Evidence shows that the PCF is a rich reservoir for various hormones, cytokines, adhesion molecules, and multiple other substances. This review aims to better understand the pericardial microenvironment, focusing on the kinetic and dynamic changes that govern different inflammatory molecules in the PCF in patients undergoing cardiac surgery. Our electronic search yielded 7 studies that reported the changes in PCF levels of interleukin (IL)-1, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)α, interferon (IFN)γ, and vascular endothelial growth factor (VEGF) during or in the immediate postoperative period after cardiac surgery. Although it was not possible to make direct comparisons of inflammatory marker levels across studies because of inconsistencies in their reporting, we aimed to identify dynamic changes in pericardial levels of these inflammatory mediators, with a focus on their potential role in the development of postoperative inflammatory response.