This chapter considers biased signaling as a natural function of G protein-coupled receptors (GPCRs) in the form of probe dependence. Thus, any ligand that changes the conformation of the receptor (agonist, antagonist, or allosteric modulator) has the potential to change the natural signaling of the receptor through unequal conformational alterations in the receptor structure. This gives an added dimension to agonist selectivity beyond extracellular recognition, namely the ability of agonists to emphasize certain signaling pathways in the cell at the expense of others. Given this, selectivity is discussed in terms of varying intrinsic efficacy and selective stabilization of receptor states with methods to detect and measure these effects. Last, the translation of in vitro to complex in vivo systems will be considered.