Fluoropyrimidines (5-fluorouracil and capecitabine) are antimetabolite drugs, widely used for the treatment of a variety of cancers, both in adjuvant and in metastatic setting. Although the most common toxicities of these drugs have been extensively studied, robust data and comprehensive characterization still lack concerning fluoropyrimidine-induced cardiotoxicity (FIC), an infrequent but potentially life-threatening toxicity. This review summarizes the current state of knowledge of FIC with special regard to proposed pathogenetic models (coronary vasospasm, endothelium and cardiomyocytes damage, toxic metabolites, dihydropyrimidine dehydrogenase deficiency); risk and predictive factors; efficacy and usefulness in detection of laboratory markers, electrocardiographic changes and cardiac imaging; and specific treatment, including a novel agent, uridine triacetate. The role of alternative chemotherapeutic options, namely raltitrexed and TAS-102, is discussed, and, lastly, we overview the most promising future directions in the research on FIC and development of diagnostic tools, including microRNA technology.