The gonadotropin hormones chorionic gonadotropin, luteinizing hormone and follicle-stimulating hormone are heterodimers that consist of a common α subunit noncovalently associated with a hormone-specific β subunit. Site-directed mutagenesis and gene transfer techniques have been invaluable tools for elucidating structure–function determinants of these hormones. Here, we review how questions about the structural biology of these glycoprotein hormones have provided crucial information for creating analogs (agonists and antagonists) that can be used to treat infertility in the clinic. The ability to manipulate the protein structure of these hormones will enable the engineering of both long- and short-acting therapeutic agents.