Several lines of evidence support a genetic predisposition to spontaneous preterm labour and preterm birth. Firstly, a leading risk factor for spontaneous preterm labour and preterm birth is a personal or family history. If a woman previously delivered preterm, her subsequent babies are also more likely to be born preterm. Women who experienced an early preterm birth (<32 completed weeks) in their first pregnancy have the highest rate of recurrent preterm birth in subsequent pregnancies. Spontaneous preterm labour and preterm birth in subsequent pregnancies tend to recur at equivalent gestational ages. If a woman herself was born preterm, she is also at an increased risk of spontaneous preterm labour and preterm birth, with the risks being highest for those women who themselves were born most preterm. This predisposition does not apply to men who were born preterm. Racial predispositions to preterm birth have also been observed. Black women suffer twice the rate of preterm birth compared with Caucasians, even when confounding social and economic variables are controlled. It is well established that upper genital tract infection and/or inflammation is seen in association with spontaneous preterm labour and preterm birth. Previous investigations have focussed primarily on an infectious aetiology for this finding. However, an alternative hypothesis has emerged, which suggests that this finding may represent an abnormal inflammatory response. The frequent association of spontaneous preterm labour and preterm birth with histological infection/inflammation and elevated body fluid concentrations of inflammatory cytokines has focussed investigations on single gene polymorphisms of these cytokines in both mother and fetus. The polymorphisms tumour necrosis factor-α-308 (TNF-α-308), interleukin-1 (IL-1) + 3953/3954 and IL-6–174 have been most consistently associated with spontaneous preterm labour and preterm birth. Toll-like receptors (TLRs) are important components of the innate immune systems, which have also been linked to spontaneous preterm labour and preterm birth. Both maternal and fetal polymorphisms of the TLR-4 gene have been associated with spontaneous preterm labour and preterm birth in certain populations, but in others no apparent link has been observed. These findings confirm a clear genetic predisposition to spontaneous preterm labour and preterm birth and raise hopes that patient-specific therapies may be developed in the future.