Nosocomial pneumonia (NP), including its subtype ventilator-associated pneumonia (VAP), represents a major cause of morbidity, mortality, and increased healthcare utilization in hospitalized patients, particularly in intensive care settings. This comprehensive, question-and-answer formatted review synthesizes current evidence on the epidemiology, pathophysiology, and management of NP and VAP, with a focus on multidrug-resistant organisms (MDROs). Key distinctions between NP and VAP are explored in terms of microbiological profiles, diagnostic approaches, and therapeutic implications. The review provides a detailed analysis of risk factors for MDROs – including prolonged mechanical ventilation, prior antibiotic exposure, and host-related immunosuppression – emphasizing the importance of risk stratification in guiding empirical antibiotic selection. A critical appraisal of international guideline recommendations (IDSA/ATS, ERS, SEPAR) highlights areas of consensus and divergence, particularly regarding empirical treatment strategies and the role of narrow- versus broad-spectrum coverage. The integration of rapid molecular diagnostic tools, such as multiplex PCR, is discussed in depth, including their potential to improve diagnostic yield, facilitate early de-escalation, and enhance antimicrobial stewardship. Recent advances in antimicrobial development are reviewed, covering novel β-lactam/β-lactamase inhibitor combinations and siderophore cephalosporins with activity against ESBL−, KPC−, and carbapenemase-producing pathogens. Their appropriate use in critically ill patients is contextualized within the framework of pharmacokinetic/pharmacodynamic optimization. Finally, the review examines current evidence on treatment duration, supporting a 7–8 day course in most cases, with individualized extension in selected high-risk populations. The utility of procalcitonin as a biomarker to guide antibiotic discontinuation is also addressed. This review provides clinicians with a concise, evidence-based reference to inform the complex decision-making required in managing nosocomial pneumonia in the era of antimicrobial resistance.