Antimicrobial resistance is expected to increase the burden of osteomyelitis drastically. The rise in resistant bacterial strains is driving researchers to find new treatment options. As a potential new antibiotic class, antimicrobial peptides (AMPs) combine several attractive intrinsic properties. Their minimal propensity for inducing antimicrobial resistance could be of particular clinical significance. AMPs act as an essential part of the innate immune system and have been identified in virtually all forms of life. These short, positively charged peptides have a combined pore-forming and intracellular killing effect on a broad range of microorganisms. Their reported spectrum of action includes resistant bacterial strains, viruses, and fungi. Moreover, immunomodulating, antitumoric, and angiogenic mechanisms have been reported. We have designed degradable and nondegradable drug-release systems for local treatment with AMPs. In animal models of osteomyelitis, these systems reduced bone infection caused by both resistant and nonresistant strains. The systemic application of several peptides for experimental detection and treatment of bone and soft-tissue infection is also discussed in this review. Radioactive-labeled peptides have accurately discriminated sterile inflammation from active infection in imaging studies. Successful preclinical studies of AMPs indicate that clinical evaluation of these powerful antibiotic agents is in order.