Antimicrobial agents are among the most common therapeutics prescribed to children and adolescents with hematologic/oncologic disorders. Because of the polymorbid state of most patients, they are frequently administered concomitantly with other drugs, resulting in a considerable potential for drug interactions. While many of these interactions are of marginal clinical significance, others are associated with substantial risks of decreased therapeutic efficacy or increased drug toxicity. Prevention and recognition of drug interactions are therefore of vital importance to optimizing effective use of antimicrobials and enhancing patient outcome. Key to minimize drug interactions are a thorough understanding of the pharmacology of frequently used antimicrobial agents and a careful evaluation of risks and benefits of potentially interacting drugs. This article reviews mechanisms and clinical relevance of drug interactions of antimicrobial agents in the supportive care of children and adolescents with hematologic/oncologic disorders and provides strategies for their prevention.