Extracellular signal-related kinase (ERK1/2 or p42/44) is a kinase in the mitogen-activated protein kinase (MAPK) family and phosphorylation of ERK (p-ERK) can be used as a common end point measurement for the activation of many classes of G protein coupled receptors (GPCR). This chapter addresses the use of PerkinElmer’s AlphaScreen® SureFireTMassay to measure ERK phosphorylation. This chapter is intended to assist in the development and optimization of p-ERK assays by providing sample protocols, factors to consider during assay optimization and data analysis details for the agonist and antagonist modes.