Patient monitoring following heart transplantation aims to detect complications (eg, acute graft rejection, vasculopathy, infection) early and contributes to risk prognostication. Numerous biomarkers of different biologic pathways have been evaluated as ancillary diagnostic and prognostic tools to reduce the need for invasive and expensive technical investigations. With the possible exception of cardiac troponins and N-type natriuretic peptides, no biomarkers have become established firmly in posttransplant patient surveillance. This article aims to show that the identification of a single biomarker that meets all needs (noninvasive diagnosis of rejection, prediction of transplant vasculopathy, survival prognostication) is unlikely. Rather, multiple marker strategies, including gene-based tests, are likely to enhance future monitoring quality and enable individualized risk-adapted patient management.