Antibiotic resistance is a global epidemic, becoming increasingly pressing due to its rapid spread. There is thus a critical need to develop new therapeutic approaches. In addition to searching for new antibiotics, looking into existing mechanisms of natural host defense may enable researchers to improve existing defense mechanisms, and to develop effective, synthetic drugs guided by natural principles. Histones, primarily known for their role in condensing mammalian DNA, are antimicrobial and share biochemical similarities with antimicrobial peptides (AMPs); however, the mechanism by which histones kill bacteria is largely unknown. Both AMPs and histones are similar in size, cationic, contain a high proportion of hydrophobic amino acids, and possess the ability to form alpha helices. AMPs, which mostly kill bacteria through permeabilization or disruption of the biological membrane, have recently garnered significant attention for playing a key role in host defenses. This chapter outlines the structure and function of histone proteins as they compare to AMPs and provides an overview of their role in innate immune responses, especially regarding the action of specific histones against microorganisms and their potential mechanism of action against microbial pathogens.