This chapter explains that penicillin was the first naturally occurring antibiotic to be characterized and used in clinical medicine. It can be seen as the progenitor of the β-lactam family of antibiotics, which are characterized by the possession of the four-membered β -lactam ring. Penicillins were originally detected in fungi but subsequently were found in streptomycetes. The cephalosporins, second member of the β -lactam antibiotic family, were also originally discovered in fungi but later detected in streptomycetes. At present, p-lactam antibiotics can be classified into several groups according to their structure: penicillins (penams), cephalosporins (cephems), cephamycins, oxacephems, penems, clavulanic acid, thienamycin (carbapenems), nocardicins, and monobactams. The chapter highlights that large number of nuclear analogs of the β -lactam antibiotics have been prepared by complete chemical synthesis or by partial synthesis starting from a naturally occurring β -lactam. Of these only the oxacephems and the penems have been investigated clinically.