Disorders of iron metabolism pose a global health challenge. Over the past two decades, novel regulators of systemic iron homeostasis have been identified that can be manipulated for therapeutic purposes. In this context, inbred and genetically modified mice have proven to be valuable tools enabling precise investigation of gene functions and testing of new pharmacological treatments that in some cases have reached the clinical stage. Here, we summarize the most recent discoveries on mechanisms regulating systemic iron homeostasis, with a specific focus on the role of murine models in advancing this research.