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Critical illness leads to significant pathophysiological changes, particularly in the case of patients with sepsis or septic shock. Activation of systemic inflammatory mediators promotes endothelial leak, extravascular fluid shifts, and overall hemodynamic instability. As the critical illness progresses, redirection of blood flow occurs to the vital organs leading to poor peripheral perfusion. Aggressive critical care management to ensure hemodynamic stability by fluid resuscitation, administration of inotropes, and vasopressors, as well as commencement of artificial organ supports, all may complicate drug therapy in critically ill patients. Drug absorption, distribution, elimination, and/or metabolism may each be significantly affected in certain cute pathologies associated with critical illness. Changes in drug pharmacokinetics may lead to treatment failure. As such, drug-dosing adjustment is required through various approaches based on the clinical condition to ensure effective drug therapy. Applying the “best” approach to pharmacy practice in the intensive care unit (ICU) setting will enhance the delivery of optimal pharmaceutical care in critically ill patients.