The role of single-agent versus combination antimicrobial therapy continues to evolve based on the avoidance of toxicity, unnecessary health care expenditures, and emergence of resistance. Tigecycline is a first-in-class glycylcycline with broad-spectrum activity against gram-negative and gram-positive aerobes, anaerobes, and multidrug-resistant pathogens. It is approved in North America, the European Union, and Latin America as monotherapy for complicated skin and skin structure infections (cSSSI) and complicated intraabdominal infections (cIAI). In licensing studies, tigecycline single-agent therapy was compared with vancomycin plus aztreonam (cSSSI) and to imipenem-cilastatin monotherapy (cIAI). Tigecycline proved noninferior to the comparators in all studies. Against community-acquired methicillin-resistant Staphylococcus aureus strains (cSSSI), tigecycline had minimum inhibitory concentration (MIC) of 0.5 μg/mL or lower for 89 of 91 isolates. In the cIAI trials, tigecycline was noninferior to imipenem-cilastatin in patients with polymicrobial infections. Rates of persistent infection did not differ between the 2 arms. Recent results of ongoing worldwide analyses such as the Tigecycline Evaluation and Surveillance Trial, and individual case reports from widespread geographic regions, continue to demonstrate the in vitro and clinical efficacy of tigecycline against pathogens causing progressively serious infections confronting clinicians worldwide. For currently approved indications and susceptible pathogens, tigecycline is an effective choice for single-agent therapy.