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This type of therapy includes different molecules such as growth factors, immune modulators, vaccines, and monoclonal antibodies (mAbs). In recent years, biologicals have been increasingly developed and authorized, although their use in children is limited compared to that in adults, due to the complexity of the pharmacokinetics and pharmacodynamics of the involved proteins, as well as other factors, such as regulations governing clinical trials. Regardless, biologicals are used with efficacy in children to treat various diseases, including oncological, hematological, atopic, and rheumatological diseases. In parallel with the increased use of biologicals, there has been an increase in the unwanted effects of these agents. This paper aims to provide physicians with a practical approach to differentiate between\u00a0the types of reactions to biologicals in children, especially mAbs, based on the frequency of use, for a comprehensive allergy workup. Starting from a clinical case (i.e., phenotype), specific biomarkers of the involved molecular mechanism (i.e., endotype) are described, providing the reader with currently known instruments to guide the diagnosis. 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