Spontaneous preterm birth is a syndrome with many causes and thus unresponsive to a single intervention. It logically follows that patients with a prior spontaneous preterm birth are a heterogeneous group unlikely to respond equally to a single preventive intervention such as 17-α hydroxyprogesterone caproate. Further confounding this issue is our fundamental lack of knowledge about the mechanism(s) by which 17-α hydroxyprogesterone caproate reduces preterm birth. Recently, studies demonstrating that responders and nonresponders can be identified based on obstetric history, genotype, physical characteristics, and behavioral factors have begun to provide clues into both 17-α hydroxyprogesterone caproate's mechanism and the pathophysiology of recurrent preterm birth and may allow for more targeted therapy. These studies lend support to speculation that inflammation or nitric oxide metabolism may be common threads between 17-α hydroxyprogesterone caproate's mechanism and preterm birth prevention. It will remain critically important to avoid the temptation to regard prior spontaneous preterm birth as a single disease entity amenable to a single treatment.