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Infectious mononucleosis (IM) is a common medical condition that afflicts thousands of young athletes each year. Despite the self-limited nature of this disorder, the variability of the clinical presentation and the rare risk of splenic rupture routinely present sports medicine clinicians with difficult return-to-play decisions. Currently there are no evidence-based guidelines regarding the management of the athlete with IM. This review discusses the available research data pertaining to the management of IM in young athletes and develops questions for future clinical research.