Lysins are a new and novel class of anti-infectives derived from bacteriophage (or phage ). They represent highly evolved enzymes produced to cleave essential bonds in the bacterial cell wall peptidoglycan for phage progeny release. Small quantities of purified recombinant lysin added externally to gram-positive bacteria results in immediate lysis causing log-fold death of the target bacterium. Lysins can eliminate bacteria both systemically and topically, from mucosal surfaces and biofilms, as evidenced by experimental models of sepsis, pneumonia, meningitis, endocarditis, and mucosal decolonization. Furthermore, lysins can act synergistically with antibiotics by resensitizing bacteria to non-susceptible antibiotics. The advantages over antibiotics are their specificity for the pathogen without disturbing the normal flora, the low chance of bacterial resistance, and their ability to kill colonizing pathogens on mucosal surfaces, a capacity previously unavailable. Lysins, therefore, may be a much-needed anti-infective in an age of mounting antibiotic resistance.