Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.