EGF receptor activation requires both ligand-binding and receptor-mediated dimerization through receptor domain II. The relationship between these processes, however, remains unclear. We have decoupled these processes to examine the ligand-binding affinity and the structure of constitutively-monomeric and -dimeric forms of the EGF receptor, as well as EGF receptor that dimerizes upon ligand-binding. Surprisingly, monomeric receptor binds to the ligands EGF and TGFα with an affinity equivalent to that of dimerizing receptor but with a unique binding enthalpy. This shows that monomeric, ligated EGF receptor adopts a state that is distinct from that of EGF receptor within a homodimer, and this state may be relevant to heterodimeric ErbB signaling complexes. Constitutively-dimerized receptor binds ligand with elevated affinity; however, it still requires ligand to form the receptor domain II dimeric interface. In the absence of ligand, no ordered, receptor domain II-mediated dimer interface is formed. Thus, the affinity effect does not arise from any pre-organization or stabilization of the ligand-binding sites on the receptor, but rather through an entropic effect of enforcing dimerization. Thus, pre-formed human receptor dimers require allosteric activation by ligand in order to signal, and this allosteric mechanism is distinct from that we recently observed for the D. melanogaster EGF receptor. Our observations on the allosteric mechanism of EGF receptor activation prompted us to ask whether other EGF receptor ligands may exert unique allosteric effects. To this end, we investigated the allosteric effects of the ligands Amphiregulin, Epiregulin, and Epigen on EGF receptor. We report that Epiregulin and Epigen, in particular, exert unique allosteric regulation on the receptor, as evidenced by divergent effects of EGFR variants on ligand-binding. Finally, we have studied ligand-binding and dimerization of receptors bearing activating extracellular mutations that cause glioblastoma. We report that these mutations elevate ligand-binding affinity, but they do not drive receptor dimerization. Our findings inform a revised model of ligand-induced receptor activation, in which the dimerization interface is highly sensitive to the presence and the identity of the bound ligand, and the domain I/domain II interface plays a crucial auto-inhibitory role.