Splenic pathophysiology has been relatively unstudied, but recently, the spleen has received more attention as a result of the discovery of the ‘cardiosplenic axis’. This term describes a role that the spleen plays in the progression of atherosclerosis following acute myocardial infarction. Human studies of this axis have largely used fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT to quantify peri-infarction inflammation, arterial wall inflammation and splenic metabolic activity. Most of these studies have quantified arterial wall inflammation and splenic metabolic activity using the standardized uptake value, but this is a semiquantitative measurement with several drawbacks, including overestimation of metabolic activity in overweight individuals and a dependence on blood glucose levels. A better approach to the measurement of metabolic activity using 18F-FDG is to measure tissue 18F-FDG clearance from dynamic imaging and Patlak–Rutland graphical analysis. This is the preferred approach for future human studies of the cardiosplenic axis that will be required to better define the nature of the spleen’s role.