Almost two million Americans per year develop hospital-acquired infections, resulting in 99,000 deaths, the vast majority of which are due to antibiotic-resistant pathogens. Because of the pressing public concern over the emergence and global spread of MDR Gram-positive bacteria, as well as the serious and life threatening nature of these diseases and the limitations of current available antibiotics, global efforts are now focused on the development of novel and alternative antibacterial. One very promising new class of antimicrobial agents includes members of a widespread family of bacteriophage-encoded, bacterial cell wall-hydrolytic enzymes, or lysins. Lysins represent a new class of antibacterial agents against Gram-positive bacteria including multidrug-resistant bacteria, with a mechanism of action distinct from antibiotics. In this review, we will describe the nature of phage lysins, how they are distinguished from antibiotics, and how they may be applied to human medicine. Finally, we will discuss the hurdles to developing a new antimicrobial class and bringing it from the lab bench to the market.