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The histamine H 1 receptor (H 1 R) is a G protein-coupled receptor (GPCR) and plays a key role in allergic reactions upon activation by histamine which is locally released from mast cells and basophils. Consequently, H 1 R is a well-established therapeutic target for antihistamines that relieve allergy symptoms. H 1 R signals via heterotrimeric G q proteins and is phosphorylated by GPCR kinase (GRK) subtypes 2, 5, and 6, consequently facilitating the subsequent recruitment of β-arrestin1 and/or 2. Stimulation of a GPCR with structurally different agonists can result in preferential engagement of one or more of these intracellular signaling molecules. To evaluate this so-called biased agonism for H 1 R, bioluminescence resonance energy transfer (BRET)-based biosensors were applied to measure H 1 R signaling through heterotrimeric G q proteins, second messengers (inositol 1,4,5-triphosphate and Ca 2+ ), and receptor-protein interactions (GRKs and β-arrestins) in response to histamine, 2-phenylhistamines, and histaprodifens in a similar cellular background. Although differences in efficacy were observed for these agonists between some functional readouts as compared to reference agonist histamine, subsequent data analysis using an operational model of agonism revealed only signaling bias of the agonist Br-phHA-HA in recruiting β-arrestin2 to H 1 R over G q biosensor activation.