Catastrophic sports injuries are rare but tragic events. Direct (traumatic) catastrophic injury results from participating in the skills of a sport, such as a collision in football. Football is associated with the greatest number of direct catastrophic injuries for all major team sports in the United States. Pole vaulting, gymnastics, ice hockey, and football have the highest incidence of direct catastrophic injuries for sports in which males participate. In most sports, the rate of catastrophic injury is higher at the collegiate than at the high school level. Cheerleading is associated with the highest number of direct catastrophic injuries for all sports in which females participate. Indirect (nontraumatic) injury is caused by systemic failure as a result of exertion while participating in a sport. Cardiovascular conditions, heat illness, exertional hyponatremia, and dehydration can cause indirect catastrophic injury. Understanding the common mechanisms of injury and prevention strategies for direct catastrophic injuries is critical in caring for athletes.