Transrectal ultrasound-guided needle biopsies (TGBs) are the mainstay of prostate cancer diagnosis. An average of 72,500 TGBs were performed in England and Wales in 2008. Current guidelines recommend fluoroquinolone prophylaxis for TGBs. However, emerging fluoroquinolone resistance has led to increased frequency and morbidity due to post-TGB infections. Following TGB, 2.15%-3.6% of patients are readmitted with infective complications. We estimate readmissions result in 25,745-37,062 bed days at an annual cost of £ 7.7-11.1 million in England and Wales. Clearly, an increase in post-TGB infections with resistant organisms has a profound clinical and economic impact. We suggest alternative approaches to prophylaxis to reduce post-TGB infections. These include prophylaxis based on local antibiotic resistance surveillance and targeted prophylaxis based on antibiograms of coliforms detected in pre-biopsy rectal swabs. Other strategies include selective prostate-specific antigen (PSA) screening and the use of biomarkers like prostate cancer antigen 3 (PCA3) to reduce the number of TGBs. Furthermore, transperineal biopsy has been shown to be associated with fewer infections.