Cyclophosphamide (CP) is an important anticancer drug which belongs to the class of alkylating agent. Cyclophosphamide is mostly used in bone marrow transplantation, rheumatoid arthritis, lupus erythematosus, multiple sclerosis, neuroblastoma and other types of cancer. Dose-related cardiotoxicity is a limiting factor for its use. CP-induced cardiotoxicity ranges from 7 to 28% and mortality ranges from 11 to 43% at the therapeutic dose of 170-180 mg/kg, i.v. CP undergoes hepatic metabolism that results in the production of aldophosphamide. Aldophosphamide decomposes into phosphoramide mustard & acrolein. Phosphoramide is an active neoplastic agent, and acrolein is a toxic metabolite which acts on the myocardium and endothelial cells. This is the first review article that talks about cyclophosphamide-induced cardiotoxicity and the different signaling pathways involved in its pathogenicity. Based on the available literature, CP is accountable for cardiomyocytes energy pool alteration by affecting the heart fatty acid binding proteins (H-FABP). CP has been found associated with cardiomyocytes apoptosis, inflammation, endothelial dysfunction, calcium dysregulation, endoplasmic reticulum damage, and mitochondrial damage. Molecular mechanism of cardiotoxicity has been discussed in detail through crosstalk of Nrf2/ARE, Akt/GSK-3β/NFAT/calcineurin, p53/p38MAPK, NF-kB/TLR-4, and Phospholamban/SERCA-2a signaling pathway. Based on the available literature we support the fact that metabolites of CP are responsible for cardiotoxicity due to depletion of antioxidants/ATP level, altered contractility, damaged endothelium and enhanced pro-inflammatory/pro-apoptotic activities resulting into cardiomyopathy, myocardial infarction, and heart failure. Dose adjustment, elimination/excretion of acrolein and maintenance of endogenous antioxidant pool could be the therapeutic approach to mitigate the toxicities.