Periprosthetic joint infection (PJI) will emerge as one of the most important issues for both orthopedic surgeons and researchers active in the field over the coming decades. Although the rate of PJI has not changed significantly over the past decade, the affected patients (hosts) being treated often present with more comorbidities than in the past, and the organisms responsible for these infections are evolving to become more difficult to treat. Fortunately, though, major strides in basic, translational, and clinical research have occurred in recent years that have armed the clinician with an armamentarium of techniques and technologies to better diagnose, prevent, and treat PJI. Advances in diagnostics, including refinements in established biomarkers, the introduction of point of service tests, developments in molecular techniques, and new techniques in advanced imaging will allow us to correctly identify the infecting pathogens and their virulence factors. Utilizing developed risk indexes to stratify and medically optimize our patients, modifying implants to incorporate antimicrobial and anti-biofilm properties, and developing clinically applicable vaccines and biofilm inhibiting enzymes will address our struggles in preventing PJI. Success of our future treatment strategies will hinge on refining the indications and technique of our current surgical procedures as well as the rational use of biofilm disrupting technologies and photodynamic therapy. Finally, the field of metabolomics, though still relatively in its infancy, likely holds the key to a novel diagnostic and treatment approach to infection and a more profound understanding of the pathophysiology of PJI on the human body.