Therapeutic considerations for aspiration pneumonia prioritize the risk of multidrug-resistant organisms. This involves integrating microbiological insights with each patient's unique risk profile, including the location at the time of aspiration, and whether it occurred in or out of the hospital. Our understanding of the microbiology of aspiration pneumonia has also evolved, leading to a reassessment of anaerobic bacteria as the primary pathogens. Emerging research shows a predominance of aerobic pathogens, in both community and hospital-acquired cases. This shift challenges the routine use of broad-spectrum antibiotics targeting anaerobes, which can contribute to antibiotic resistance and complications such as Clostridium difficile infections—concerns that are especially relevant given the growing issue of antimicrobial resistance. Adopting a comprehensive, patient-specific approach that incorporates these insights can optimize antibiotic selection, improve treatment outcomes, and reduce the risk of resistance and adverse effects.