Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including “How important is protein binding?”, “Is protein binding always constant?”, “Do pH and temperature changes alter binding?” and “How do protein binding changes affect dosing requirements?”. In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (Vd), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.