Recent advances in our understanding of the pluridimensional nature of GPCR signaling have provided new insights into how orthosteric ligands regulate receptors, and how the phenomenon of functional selectivity or ligand "bias" might be exploited in pharmaceutical design. In contrast to the predictions of simple two-state models of GPCR function, where ligands affect all aspects of GPCR signaling proportionally, current models assume that receptors exist in multiple "active" conformations that differ in their ability to couple to different downstream effectors, and that structurally distinct ligands can bias signaling by preferentially stabilizing different active states. The type 1 parathyroid hormone receptor (PTH(1)R) offers unique insight into both the opportunities and challenges of exploiting ligand bias in pharmaceutical design, not only because numerous "biased" PTH analogs have been described but also because many of them have been characterized for biological activity in vivo. The PTH(1)R has pleiotropic signaling capacity, coupling to G(s), G(q/11), and G(i/o) family heterotrimeric G proteins, and binding arrestins, which mediate receptor desensitization and arrestin-dependent signaling. Here, we compare the activity of six different PTH(1)R ligands in a common HEK293 cell background using three readouts of receptor activation, cAMP production, intracellular calcium influx, and ERK1/2 activation, demonstrating the range of signal bias that can be experimentally observed in a "typical" screening program. When the in vitro activity profiles of these ligands are compared to their reported effects on bone mass in murine models, it is apparent that ligands activating cAMP production produce an anabolic response that does not correlate with the ability to also elicit calcium signaling. Paradoxically, one ligand that exhibits inverse agonism for cAMP production and arrestin-dependent ERK1/2 activation in vitro, (D-Trp(12), Tyr(34))-bPTH(7-34), reportedly produces an anabolic bone response in vivo despite an activity profile that is dramatically different from that of other active ligands. This underscores a major challenge facing efforts to rationally design "biased" GPCR ligands for therapeutic application. While it is clearly plausible to identify functionally selective ligands, the ability to predict how bias will affect drug response in vivo, is often lacking, especially in complex disorders.