The management of infections of the cardiac structures-specifically native heart valvesremains a difficult clinical challenge. Patients often present with a systemic infection that is made worse by embolic complications, such as strokes, along with pathophysiologic sequelae of acute valvular dysfunction. The timing of interventions has a significant impact on short-and long-term outcomes. The challenges and management decisions are even more complex when the infection involves a prosthetic valve-as risks of reoperative cardiac surgery can be substantial. The goal of this chapter is to discuss the history of prosthetic valve endocarditis, review the current literature on the management of specific valvular involvement (i.e., aortic and/or mitral), and illustrate the challenging problems and outcomes that drive clinical decision making. While many of the indications for surgery are similar to those associated with native valve infections, there is increased risk with reoperative surgery, often difficulties in clearing infection due to prosthetic material being in place. Unfortunately, antibiotics alone are not always effective, and frequent communications between the cardiac surgeon and infectious disease physicians are often necessary to find the "sweet spot" to perform the surgery.