Ideal tests of the effects of therapeutic interventions measure the desired outcomes; however, the desired outcomes are not always easily measured or may be long-term objectives. Biomarkers and surrogate end-points are often cheaper and easier to measure and can be measured over a shorter time span. They can be used in screening, diagnosing, staging, and monitoring diseases, in monitoring responses to interventions, and in various aspects of drug discovery and development. They can be extrinsic to the body or intrinsic, and can relate to any point in the pharmacological chain, at the molecular, cellular, tissue, or organ level. Problems arise when the relation between the pathophysiology of the disease and the mechanism of action of the intervention is not properly understood; when adverse effects obviate therapeutic effects; when confounding factors, such as other drugs, alter the surrogate independently of the final end-point; when a biomarker persists after resolution of the disease; and when the concentration–effect curves for the effects of an intervention on the primary outcome and the surrogate are different. Use of biomarkers may also be hindered by poor reproducibility of measurement techniques. Challenges for clinical pharmacologists are to devise biomarker tests that are reliable, reproducible, sensitive, and specific, and surrogate end-points that are associated with the clinical outcomes of concern and useful. A robust taxonomy is needed of the relations that link the pathophysiology of disease, the mechanisms of action of interventions and their adverse effects, the desired clinical outcomes, and the surrogate end-points that predict them.