In athletes with upper respiratory infections (URIs), the question of who plays and who sits can be difficult to answer. Acute exercise suppresses several aspects of the immune system. None of these immunologic changes, however, consistently correlate with the incidence of URIs in athletes. The risk of infection with exercise seems to follow a J-curve relationship, with regular, moderate exercisers having a lower risk than sedentary people, and regular, strenuous exercisers having the highest risk of all. The decision to allow an athlete to play or not can be guided by the "neck check" rules, and can also take into account nonmedical factors. The athlete with infectious mononucleosis warrants more careful attention, as there are strict guidelines for return-to-play in these individuals, to avoid the possibility of splenic rupture.