Immunogenicity of biological agents leads to the development of antidrug antibodies (ADA) and it may be associated to hypersensitivity reactions. Immediate infusion reactions occur during or within 1 h after infusion, and their clinical manifestations vary considerably, ranging from mild to severe and life-threatening. Recent studies show that different mechanisms sustain hypersensitivity reactions toward biologics, and the application of novel methods for detecting ADA has demonstrated the involvement of specific IgE isotypes. Considering the severity of the reactions, it is important for clinicians to recognize their symptoms, to know their pathophysiological mechanisms, and to take risk assessment and prophylactic procedures. This review summarizes the clinical manifestations of antibody and nonantibody-mediated reactions as well as the humoral and cellular mechanisms of antidrug responses. Last, the management of patients at risk is discussed. The definition of diagnostic and prophylactic strategies represents an unavoidable need in the management of potentially reactive patients to improve the safety profile of biologics.