Beta-lactams are a group of antibiotics with a broad spectrum of both Gram-negative and Gram-positive coverage. The goal of this study is to evaluate the results from studies regarding Ig-E mediated hypersensitivity to Penicillin and cross-reactivity with other beta-lactams. Review was conducted of both retrospective and prospective studies by searching in PubMed and Medline for the original and systematic review articles by using the keywords: penicillin allergy, beta-lactams and cross-reactivity. The rate of true Penicillin allergy is about 10% of reported cases by the patients. The rate of Ig-E mediated cross-reactivity between Penicillin and Cephalosporins is less than 10% for the first and second generations and less than 5% for the third and fourth generations. According to the reviewed studies, Imipenem has between 9.2% to 25.6% cross- reactivity with Penicillin. Recent studies have shown safe use of Meropenem in patients with penicillin allergy even with positive skin test. The only member of Monobactam family, Aztreonam, has no cross-reactivity with any of Penicillins, Cephalosporins (with the exception of Ceftazidime) and Carbapenems. Due to the low rate of true Penicillin allergy, the patient’s self report of this adverse reaction must be justified carefully before avoiding beta-lactams. Even in the cases of true penicillin allergy, Meropenem appears to be safe, if indicated. There are also a few case reports regarding hypersensitivities to Clavulanate itself and also its cross-reactivity with Penicillin.