Since September 11, 2001, the Centers for Disease Control and Prevention (CDC) has increased efforts to prepare the agency and public health partners for response to potential nuclear/radiological disasters. During the week of May 16–20, 2022, the CDC participated in a national-level radiological emergency exercise, Cobalt Magnet 22 (CM22). The exercise scenario consisted of a notional, failed search mission for a radiological dispersal device (RDD, “dirty bomb”), followed by its explosion during a public event in a large US city. Testing radioanalytical laboratory capabilities during a nuclear/radiological incident was an exercise objective, and developing clear messaging on low-dose exposure and long-term health concerns was a primary output of the exercise. The CDC practiced its activation protocols, exercised the establishment of its updated Incident Management System structure for radiation emergencies, and identified critical staffing needs for this type of response.