Early initiation of effective antibiotic therapy is vitally important for saving the lives of critically ill patients with sepsis or septic shock. The susceptibility of the infecting pathogen and the ability of the selected dosage regimen to safely achieve the required antibiotic exposure need to be carefully considered to achieve a high probability of a successful outcome. Critically ill patients commonly experience substantial pathophysiological changes that impact the functions of various organs, including the kidneys. Many antibiotics are predominantly renally eliminated and thus renal function is a major determinant of the regimen needed to achieve the required antibiotic exposure. However, currently, there is a paucity of guidelines to inform antibiotic dosing in critically ill patients, including those with sepsis or septic shock. This paper briefly reviews methods that are commonly used in critically ill patients to provide a measure of renal function, and approaches that describe the relationship between the exposure to an antibiotic and its antibacterial effects. Two common conditions that very substantially complicate the use of antibiotics in critically ill patients with sepsis, unstable renal function, and augmented renal clearance, are considered in detail and their potential therapeutic implications are explored. Suggestions are provided on how treatment of bacterial infections in critically ill patients with sepsis might be improved. Of high potential are model-informed approaches that aim to individualize initial treatment regimens based on patient and bacterial characteristics, with refinement of regimens during treatment in response to monitoring antibiotic concentrations, responsive measures of renal function, and other important clinical data.