Because of its antinociceptive effects, the μ-opioid receptor (MOR) is an important target for pain management, but serious side effects limit the use of drugs that target this GPCR. Because the MOR stimulates intracellular signaling through both G proteins and β-arrestins, G protein–biased agonists have been developed to promote pain relief without causing β-arrestin–associated side effects. Gillis et al. compared the biochemical, signaling, and physiological properties of some G protein–biased MOR agonists with those of unbiased opioids. The observed reductions in side effects could be explained by the low intrinsic efficacy of the biased agonists rather than by their signaling bias per se. These findings suggest possible strategies for developing new MOR agonists that relieve pain with fewer unwanted side effects.Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.