© 2020 by the American Society of Nephrology. Bloodstream infections are an important cause of hospitalizations, morbidity, and mortality in patients receiving hemodialysis. Eliminating bloodstream infections in the hemodialysis setting has been the focus of the Centers for Disease Control and Prevention (CDC) Making Dialysis Safer for Patients Coalition and, more recently, the CDC’s partnership with the American Society of Nephrology’s Nephrologists Transforming Dialysis Safety Initiative. The majority of vascular access-associated bloodstream infections occur in patients dialyzing with central vein catheters. The CDC’s core interventions for bloodstream infection prevention are the gold standard for catheter care in the hemodialysis setting and have been proven to be effective in reducing catheter-associated bloodstream infection. However, in the United States hemodialysis catheter-associated bloodstream infections continue to occur at unacceptable rates, possibly because of lapses in adherence to strict aseptic technique, or additional factors not addressed by the CDC’s core interventions. There is a clear need for novel prophylactic therapies. This review highlights the recent advances and includes a discussion about the potential limitations and adverse effects associated with each option.