Periprosthetic joint infection has become the most common cause of failure following total knee arthroplasty. Over the past 4 decades, treatment of this disease has evolved with technological innovations and pathogen profiling. The appropriate treatment selection is dependent on patient immune system quality, timing of symptom onset, and pathogen type. Antibiotic suppression alone is reserved for those cases without drainage, low-virulent antimicrobial-susceptible pathogens, and patients whose level of health increases the risk of surgery past any risk associated with chronic infection. In patients with an acute onset of symptoms and antimicrobial-susceptible pathogens, irrigation and debridement with exchange of modular components is moderately successful and offers the advantage of component retention and maximum knee function. In failed irrigation or chronic periprosthetic joint infection, resection of all components is necessitated. Resection and reimplantation can either be performed in one or two stages. A single-stage exchange has the potential to decrease the number of surgeries and therefore cost. However, the success rate of direct exchange is lower than that of two-stage revision. This has led to two-stage revision, with the placement of an intra-stage antibiotic-loaded spacer, to become the “gold” standard for periprosthetic joint infection eradication. In an immunocompromised patient with an uncontrollable periprosthetic joint infection, salvage procedures are necessitated. Complete eradication of periprosthetic joint infection is achieved by resection of all components without reimplantation through arthrodesis or above-the-knee-amputation. While amputation may be unpopular with patients it provides a greater ability to reconstruct, with an external prosthesis, a functioning joint.