As pediatric imaging capabilities have increased in scope, so have the complexities of providing procedural sedation in this environment. While efforts by many organizations have dramatically increased the safety of pediatric procedural sedation in general, radiology sedation creates several special challenges for the sedation provider. These challenges require implementation of additional safeguards to promote safety during sedation while maintaining effective and efficient care. Multiple agent options are available, and decisions regarding which agent(s) to use should be determined by both patient needs (i.e., developmental capacities, underlying health status, and previous experiences) and procedural needs (i.e., duration, need for immobility, and invasiveness). Increasingly, combinations of agents to either achieve the conditions required or mitigate/counterbalance adverse effects of single agents are being utilized with success. To continue to provide effective imaging sedation, it is incumbent on sedation providers to maintain familiarity with continuing evolutions within radiology environments, as well as comfort and competence with multiple sedation agents/regimens. This review discusses the challenges associated with radiology sedation and outlines various available agent options and combinations, with the intent of facilitating appropriate matching of agent(s) with patient and procedural needs.