The discovery of drugs for G protein-coupled receptors (GPCRs) has traditionally been very successful, even before the structural nature of these molecular targets was elucidated. Over the years, this family of proteins has become more important in the understanding and treatment of different human pathologies, representing today close to 30% of the molecular targets of all marketed drugs. The sequencing of the human genome unveiled the existence of many new GPCRs and this has increased even more the interest of this family of proteins as potential drug targets. Today the search for compounds that interfere or modulate the function of GPCRs is one of the major focuses of pharmaceutical companies. The understanding of the molecular events that take place upon receptor activation, together with the need of testing large chemical libraries, has resulted in the development of a variety of methods and technologies to measure the activity of these receptors. In this chapter we will review most of the assay technologies currently in use for "in vitro" pharmacological screening, their evolution, their capabilities, and their limitations.