The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing. ADAMTS-13 a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13, ALAT alanine amino transferase, APACHE IV Acute Physiology and Chronic Health Evaluation-IV, aPPT activated partial thromboplastin time, ASAT aspartate amino transferase, AT antithrombin, Ca-V-O oxygen content difference, arterial-venous, CRP C-reactive protein, ELAM endothelial leukocyte adhesion molecule, ICAM intercellular adhesion molecule, IL interleukin, INR international normalized ratio, LBP lipopolysaccharide-binding protein, MCP monocyte chemoattractant protein, mHLA monocytic human leukocyte antigen, MIF migration inhibitory factor, MIP macrophage inflammatory protein, PAI plasminogen activator inhibitor, PCO partial pressure of carbon dioxide, PT prothrombin time, RRT renal replacement therapy, SAPSS III Simplified Acute Physiology Score-III, sO oxygen saturation, SOFA Sequential [Sepsis-related] Organ Failure Assessment, sTREM soluble triggering receptor expressed on myeloid cells 1, TLR toll-like receptor, TNF tumor necrosis factor, VCAM vascular cell adhesion molecule, VEGF vascular endothelial growth factor, vWf von Willebrand factor.