Piperacillin-tazobactam is a beta-lactam/beta-lactamase inhibitor combination with a broad spectrum of antibacterial activity that includes Gram-positive and -negative aerobic and anaerobic bacteria. Piperacillin-tazobactam retains its in vitro activity against broad-spectrum beta-lactamase-producing and some extended-spectrum beta-lactamase-producing Enterobacteriaceae, but not against isolates of Gram-negative bacilli harboring AmpC beta-lactamases. Piperacillin-tazobactam has recently been reformulated to include ethylenediaminetetraacetic acid and sodium citrate; this new formulation has been shown to be compatible in vitro with the two aminoglycosides, gentamicin and amikacin, allowing for simultaneous Y-site infusion, but not with tobramycin. Multicenter, randomized, double-blinded clinical trials have demonstrated piperacillin-tazobactam to be as clinically effective as relevant comparator antibiotics. Clinical trials have demonstrated piperacillin-tazobactam to be effective for the treatment of patients with intra-abdominal infections, skin and soft tissue infections, lower respiratory tract infections, complicated urinary tract infections, gynecological infections and more recently, febrile neutropenia. Piperacillin-tazobactam has an excellent safety and tolerability profile and continues to be a reliable option for the empiric treatment of moderate-to-severe infections in hospitalized patients.