In mammals, the interactions between glycoprotein hormones and their cognate receptors are highly specific; unintended cross-reactivity under normal physiological conditions has not been observed. The interactions between fish gonadotropins and their receptors, on the other hand, appeared to be less discriminatory. For example, the catfish follicle-stimulating hormone (FSH) receptor was highly responsive to both catfish luteinizing hormone (LH) and catfish FSH. Similarly, the FSH receptor of coho salmon bound both salmon FSH and LH. In contrast, LH receptors of both species were found to be rather specific for their cognate LH. This paper intends to summarize the current situation with special emphasis to our comparative structure-function studies that aim at elucidating the molecular basis of ligand selectivity (in mammals) and ligand promiscuity (in fish).