We present a protein structure-based phylogeny of Classes A, C and D of the serine beta-lactamases, and a new, detailed, sequence-based phylogeny of the Class A beta-lactamases. In addition, we discuss the historical evolution of Classes C and D. The evolutionary histories of all three classes indicate that the serine beta-lactamases are ancient enzymes, originating over two billion years ago, and that some have been on plasmids for millions of years. We also discuss the recent, antibiotic-era, evolution of the serine beta-lactamases in response to the clinical use of beta-lactam antibiotics. We also discuss a method that is being used to predict the future evolution of beta-lactamases in response to selection with new drugs.