As the backbone of oncological treatments, systemic chemotherapy is still one of the main pawns in cancer care, alone or in combination with newer targeted agents. All chemotherapy agents can be associated with a type of adverse event called an infusion reaction, which can be characterized as unpredictable, non-dose related, and unexplained by the cytotoxic profile of the drug. For some of these events, a certain immunological mechanism can be identified by blood or skin testing. In this case, we can speak of true hypersensitivity reactions that occur as a response to an antigen/allergen. The current work summarizes the main antineoplastic therapy agents and their susceptibility to induce hypersensitivity reactions and also includes a review of clinical presentation, diagnostic methods in hypersensitivity reactions, and perspectives to overcome these negative events in the treatment of patients suffering from various types of cancer.