Critically septic patients carry high mortality; however, it may be ameliorated to some extent by the appropriate prescription of antimicrobials and appropriate dosing strategy. Drug metabolism in critically septic patients differ from other less critical patients, and antimicrobial treatment need to be adjusted to prevent under dosing. The augmented clearance, acute kidney injury, microvascular ischemia, all affect antimicrobials’ levels. Methods of antimicrobial administration were explored, continuous infusion versus intermittent bolus, with the aim of maximizing drug exposure, hitherto, apart from PK/PD advantage, it was not translated clearly into patients’ clinical outcome. Biofilms have a unique management as they need elevated antimicrobial dosages to assure adequate drug exposure, and agents that work directly on biofilms to assure its disruption. Application of PK/PD knowledge in the management of critically septic patients maximize the clinical outcome and assures proper drug exposure, avoiding under dosing and drug toxicity, and decreasing the chance of antimicrobials mutant’s selection, and therapy failures