Bacteriophages must destroy the bacterial cell wall to lyse their host and release their progeny into the environment. There are at least two distinct mechanisms by which phages destroy the cell wall. Bacteriophages with large genomes use a holin-endolysin system, while bacteriophages with small genomes encode a single lysis protein. Three unrelated single protein lysis systems are known and these proteins will be the focus of the review. Recent results indicate that at least two of these proteins inhibit cell wall synthesis and are thus the phage analogs of antibiotics like penicillin.