Myocardial interstitial fibrosis (MIF) is a common finding in heart failure (HF) patients, both with preserved and reduced ejection fraction, as well as in HF animal models. MIF is associated with impaired cardiac function and worse clinical outcome. The impact of MIF is influenced not only by the quantity but also by changes in the quality of collagen fibers and in the extracellular matrix components, such as a shift in collagen types proportion, increased fibronectin polymerization and increased degree of collagen cross-linking (CCL). In particular, CCL, a process that renders collagen fibers stiffer and more resistant to degradation, is increased both in patients and animal models of HF. Importantly, in HF patients increased cardiac CCL is directly associated with increased left ventricular stiffness and a higher risk of hospitalization for HF. The aim of this review is to address the complexity of MIF in HF, focusing on CCL.