Drugs active at G protein–coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT_2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT_1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT_2B receptor bound to ERG and compared it with the 5-HT_1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.