The review discusses the toxicity mechanisms of gadolinium (Gd) and gadolinium-based contrast agents (GBCAs), which have been widely used in magnetic resonance imaging (MRI) for over three decades. GBCAs can be classified as linear or macrocyclic based on their chemical structure, with linear GBCAs being more prone to releasing Gd ions, leading to higher tissue deposition and potential toxicity. The review highlights the importance of understanding Gd toxicity, especially renal toxicity, given the increasing prevalence of chronic kidney disease and the association between GBCA exposure and renal dysfunction. The mechanisms of Gd toxicity include interference with signaling pathways such as MAPK/ERK, PI3K/Akt, and EGFR, leading to upregulation of inflammation, oxidative stress, and apoptosis. GBCAs also promote the production of reactive oxygen species, nitrate/nitrite, and prostaglandin E2, and can cause lipid peroxidation and autophagic activation. Additionally, Gd can interfere with calcium homeostasis, block ATP hydrolysis, and affect iron metabolism. The review also discusses the safety concerns associated with GBCAs, including the European Medicines Agency's (EMA) recommendations for restricting the use of certain linear GBCAs and the development of safer alternatives, such as macrocyclic GBCAs and novel formulations like nanoparticles and liposomal GBCAs. The review concludes by emphasizing the need for further research to understand the molecular and cellular mechanisms of Gd cytotoxicity and to develop counteracting therapeutic measures.The review discusses the toxicity mechanisms of gadolinium (Gd) and gadolinium-based contrast agents (GBCAs), which have been widely used in magnetic resonance imaging (MRI) for over three decades. GBCAs can be classified as linear or macrocyclic based on their chemical structure, with linear GBCAs being more prone to releasing Gd ions, leading to higher tissue deposition and potential toxicity. The review highlights the importance of understanding Gd toxicity, especially renal toxicity, given the increasing prevalence of chronic kidney disease and the association between GBCA exposure and renal dysfunction. The mechanisms of Gd toxicity include interference with signaling pathways such as MAPK/ERK, PI3K/Akt, and EGFR, leading to upregulation of inflammation, oxidative stress, and apoptosis. GBCAs also promote the production of reactive oxygen species, nitrate/nitrite, and prostaglandin E2, and can cause lipid peroxidation and autophagic activation. Additionally, Gd can interfere with calcium homeostasis, block ATP hydrolysis, and affect iron metabolism. The review also discusses the safety concerns associated with GBCAs, including the European Medicines Agency's (EMA) recommendations for restricting the use of certain linear GBCAs and the development of safer alternatives, such as macrocyclic GBCAs and novel formulations like nanoparticles and liposomal GBCAs. The review concludes by emphasizing the need for further research to understand the molecular and cellular mechanisms of Gd cytotoxicity and to develop counteracting therapeutic measures.