Two new molecular MRI agents have been approved for clinical use within the last 3 years, and a third agent has completed phase-2 clinical trials. A wealth of preclinical data is also emerging on the general safety of many molecular MR imaging agents. In addition, since the guidelines to avoid nephrogenic systemic fibrosis (NSF) were adopted, at most institutions no new cases of NSF have been reported. Nevertheless, in the post-NSF environment, both those developing and using molecular MR imaging agents need to be increasingly aware of safety issues. This awareness should begin with the design of the agent and, even in early preclinical studies, the demonstration of safety and efficacy should both be given high priority. In this review we discuss some of the issues relevant to the design of safe molecular MR imaging agents and highlight the excellent safety profile of those agents that have been used clinically to date.