One of the most serious complications following the implantation of orthopedic biomaterials is the development of infection. Orthopedic implant-related infections do not only entail clinical problems and patient suffering, but also cause a burden on healthcare care systems. Additionally, the ageing of the world population, in particular in developed countries, has led to an increase in the population above 60 years. This is a significantly vulnerable population segment insofar as biomaterials use is concerned. Implanted materials are highly susceptible to bacterial and fungal colonization and the consequent infection. These microorganisms are often opportunistic, taking advantage of the weakening of the body defenses at the implant surface–tissue interface to attach to tissues or implant surfaces, instigating biofilm formation and subsequent development of infection. The establishment of biofilm leads to tissue destruction, systemic dissemination of the pathogen, and dysfunction of the implant/bone joint, leading to implant failure. Moreover, the contaminated implant can be a reservoir for infection of the surrounding tissue where microorganisms are protected. Therefore, the biofilm increases the pathogenesis of infection since that structure offers protection against host defenses and antimicrobial therapies. Additionally, the rapid emergence of bacterial strains resistant to antibiotics prompted the development of new alternative approaches to prevent and control implant-related infections. Several concepts and approaches have been developed to obtain biomaterials endowed with anti-infective properties. In this review, several anti-infective strategies based on biomaterial engineering are described and discussed in terms of design and fabrication, mechanisms of action, benefits, and drawbacks for preventing and treating orthopaedic biomaterials-related infections.