Serum sickness-like reactions (SSLR) consist of urticaria or urticarial-like rashes with joint pain and variable features of fever, angioedema and gastrointestinal distress. Allergists typically evaluate patients in the clinic for an implicated medication, such as antibiotic or vaccine. Although SSLR may be mistaken for classical serum sickness or anaphylaxis due to overlapping clinical features, there is minimal evidence for type I or type III hypersensitivity reactions. Despite recent studies showing antibiotic allergy is rarely verified, patients rarely undergo allergy evaluation. A difficulty is that there is no agreement about challenge procedures- multiple day dosing protocols lead to a risk for hives and joint pain which does not occur with single day challenges. Additionally, tolerance of either challenge protocol does not fully prevent rashes and repeat episodes of SSLR in all non-allergic children who used the culprit or an unrelated antibiotic again. Due to the distressing symptoms, lack of abortive therapies, and uncertainty with challenge, many healthcare professionals and families may prefer to bypass allergy evaluation and continue lifelong avoidance. However, medication allergy labels may be associated with poor health outcomes. Well-designed prospective studies are needed to provide better insight into the diagnosis, effective treatments, and true recurrence rates.