Under the new cervical insufficiency postulate, the final common pathway theoretically may be influenced by multiple interventions including not only cerclage, but also antibiotics, anti-inflammatory drugs, or progesterone. Since the late 1970s, accumulating evidence has implicated intrauterine infection as a cause of preterm labor. The use of antimicrobial therapy for the prevention of preterm delivery (PTD), although plausible and appealing, has remained largely ineffective so far. A decade of antimicrobial intervention trials to prevent infection-mediated PTD has had disappointing results. Several randomized clinical trials have assessed the role of bacterial vaginosis (BV) treatment in prevention of PTD. The inconsistent results of these trials suggest that other processes, possibly immunomodulation, may be important. Additional factors, still unidentified, pertaining to infectious agent virulence or host immune response modulation, may be responsible for the increased risk of PTD in only a small subset of pregnant women with BV. Even a particular genetic susceptibility was proposed as an intervening factor in the correlation between BV and PTD. Autocrine, paracrine, and endocrine processes in the fetal-placental-uterine unit may contribute to the premature activation of parturitional mechanisms. Progesterone has been used in an attempt to prevent PTD since the 1970s, but the evidence accumulated until the 1990s was fraught by mixed results, and was based mostly on underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. Two recent randomized, controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone treatment may influence favorably the rate of preterm delivery, as well as perinatal mortality and morbidity. A major impediment in accepting progesterone as the magic bullet in the prevention of PTD is that its mechanism of action is less well understood than that of all the other prophylactic measures discussed in this review. The optimal formulation, route of administration, dose, and gestational age at initiation have yet to be established. Our ability to quantify prospectively the risk of PTD in a given patient is limited. Moreover, there are limited evidence-based strategies available for prevention of PTD, reflecting our incomplete understanding of the nature of preterm labor. Although an effective instrument in PTD prevention is still elusive, the studies conducted so far have led to a shift in our understanding of cervical insufficiency, infection-mediated PTD, and hormonal influences in human parturition.