To review the pharmacology, microbiology, efficacy, and safety of lefamulin. A literature search was performed using PubMed and Google Scholar (2010 to end-April 2020) with the search terms and . Other resources included abstracts presented at recent conferences, prescribing information, and the manufacturer's and Food and Drug Administration websites. All relevant English-language articles of studies assessing the efficacy and safety of lefamulin were included. Lefamulin is a pleuromutilin antibiotic with activity against , and atypical bacteria. Lefamulin, given at the dose of 150 mg intravenously or 600 mg orally on an empty stomach every 12 hours for 5 to 7 days, was proven noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). Common adverse reactions include injection site reactions, hepatic enzyme elevation, gastrointestinal upset, hypokalemia, insomnia, and headache. Lefamulin is associated with QT prolongation, and concomitant use with CYP3A substrates that prolong the QT interval is contraindicated. Lefamulin may cause fetal harm. Lefamulin is a novel antibiotic with a unique mechanism of action. It represents an alternative option to β-lactams and macrolides in the treatment of adults with CABP and an alternative option to amoxicillin and doxycycline in the outpatient setting given the rise in resistance to macrolides and safety concerns with fluoroquinolones. Nausea, vomiting, and diarrhea may limit the tolerability of the oral formulation. Lefamulin is the first systemic pleuromutilin antibiotic that has proven safe and effective for adults with CABP.