Allosteric modulation of G protein-coupled receptors has recently been recognized as an alternative approach to gain selectivity in drug action. In this overview, allosteric modulators that enhance or diminish the effects of (endogenous) agonists or antagonists on a variety of G protein-coupled receptors are described. Emphasis is placed on the latest developments in this research area, including data on the first clinical studies. It appears that all three major classes of G protein-coupled receptors (A, B and C) are amenable to allosteric modulation by small molecules. This constitutes an attractive and novel means to identify new leads in the drug discovery process. However, it requires a re-engineering of the majority of current assays. Finally, it is suggested to introduce the term 'non-competitive agonism' or 'allosteric agonism' next to allosteric modulation.