Purpose of Review The looming threat of antimicrobial resistance requires robust stewardship and new developments in infectious diseases pharmacotherapy. This review discusses the pertinent spectrum and clinical data of lefamulin (Xenleta®), with a focus on potential real-world use. Recent Findings Lefamulin is a novel pleuromutilin antibiotic that obtained Food and Drug Administration labeling for community-acquired bacterial pneumonia (CABP) in 2019. Lefamulin is available in both intravenous and oral formulations, and it inhibits bacterial protein synthesis inhibition through interactive binding to unique sites of the peptidyl transferase center of the 50s bacterial ribosome subunit. Resistance, including cross-resistance with other antibiotics, is infrequent. Lefamulin demonstrates activity against most Gram-positive pathogens and other organisms commonly associated with CABP, i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae. Lefamulin may also be an option for serious public health threats like methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and multi-drug-resistant organisms associated with sexually transmitted infections, e.g., Neisseria gonorrhoeae, Mycoplasma genitalium. Lefamulin lacks activity against Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacterales, most anaerobes, and E. faecalis. In Phase III trials, lefamulin monotherapy was non-inferior to moxifloxacin with or without linezolid for CABP. Summary Lefamulin is a well-tolerated agent with a unique mechanism, availability in both IV and PO formulations, and it has been rigorously studied for safety and efficacy for CABP.