This new edition combines updates of key chapters from the first edition with a large number of new key methodologies that have emerged more recently for studying G protein-coupled receptors (GPCRs) and events immediately downstream of their activation. The methods are focused primarily on events at the receptor level, including ligand binding, the genetic manipulation of receptors, the generation of model cell lines in which to study them, and the interaction and activation of G-proteins. Additional methods concentrate on receptor expression and localization, receptor internalization and post-translational modification, GPCR–protein interactions, and the use of knock-out and knock-in strategies for determining the physiological roles of receptors.