G-Protein coupled receptors (GPCRs) have been, and remain a key target of drug discovery programs for human disease. While many drugs have been developed that interact with these proteins in the simple classic manner – that is – physically blocking the cognate ligand from simply binding to its target receptor, drug discovery approaches have elucidated alternative more complex methods by which small molecules can interact with these receptors and block their function. This is most evident in the Class B GPCRs where the cognate ligands are relatively large peptides with multiple points of contact on the GPCR spanning both hydrophilic and hydrophobic domains on the same protein to elicit function. It has therefore been difficult to precisely determine not only the mechanism by which a small molecule can inhibit the function of a large peptide but also the nature of that mechanism that drives the differences in efficacy. This review will examine in detail the nature of small molecule inhibition of corticotropin-releasing factor receptors and illustrate the role that allosteric binding and kinetics play in the functional inhibition of this Class B GPCR.