While fluoroquinolones, vancomycin, macrolides, and tetracyclines are generally safe antibiotics, they can induce both immediate and delayed hypersensitivity reactions (HSRs). Historically, less has been published on allergies to these antibiotics compared to beta lactams, but the prevalence of non-beta lactam HSRs is increasing. To fluoroquinolones, immediate HSRs are more common than delayed reactions. Both IgE and non-IgE mechanisms, such as the mast cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2), have been implicated in fluoroquinolone-induced anaphylaxis. Skin testing for fluoroquinolones is controversial, and the gold standard for diagnosis is a graded dose challenge. To vancomycin, the most common reaction is vancomycin infusion reaction (previously called "red man syndrome"), which is caused by infusion rate-dependent direct mast cell degranulation. Severity can range from flushing and pruritis to angioedema, bronchospasm, and hypotension that mimic type I HSRs. MRGPRX2 has been implicated in vancomycin infusion reactions. IgE-mediated HSRs to vancomycin are rare. Vancomycin skin testing yields high false positive rates. Thus, direct provocation challenge with slower infusion rate and/or antihistamine pre-treatment is preferred if symptoms are mild to moderate, and desensitization can be considered if symptoms are severe. To tetracyclines, non-IgE-mediated and delayed HSRs predominate with cutaneous reactions being the most common. There is no standardized skin testing for tetracyclines, and avoidance is generally recommended after a severe reaction because of the paucity of data for testing. Graded dose challenges and desensitizations can be considered for alternative or index tetracyclines if there are no alternatives. With macrolides, urticaria/angioedema is the most common immediate HSR, and rash is the most common delayed HSR. The predictive value for skin testing to macrolides is similarly poorly defined. In general, HSRs to fluroquinolones, vancomycin, macrolides, and tetracyclines are challenging to diagnose given the lack of validated skin testing and in vitro testing. Direct provocation challenge remains the gold standard for diagnosis, but the benefits of confirming an allergy may not outweigh the risk of a severe reaction. Skin testing, direct provocation challenge, and/or desensitization to the index non-beta lactam antibiotic or alternatives in its class may be reasonable approaches depending on the clinical context and patient preferences.