||Spontaneous preterm birth (SPTB) is defined as birth before 37 completed weeks gestation that is not secondary to iatrogenic intervention. SPTB is both a pressing personal and public health issue that is not well understood. Previous studies have shown genetics as an important factor to SPTB. Here I present my PhD work on genetic analyses of SPTB. I dissected the problem with: (1) candidate gene, (2) quantitative genetics, and (3) genome-wide approaches. In Chapter 1, I explore why published candidate gene studies are inconsistent with each other. Allele frequency difference across populations provides one reason. I conducted a meta-analysis on the single nucleotide polymorphism (SNP) rs1800795, located in the promoter region of interleukin-6. With population stratification, I unmasked the signal showing that the CC genotype is protective against PTB in women of European descent. This also highlights how positive genetic signals can become obscured when the population structure is not controlled for. In Chapter 2, I use quantitative genetic approaches to decompose the etiologies of SPTB with massive data from the Utah Population Database. A generation effect, which confounds the heritability estimate, was discovered. I then utilized a sibling analysis and partitioned components contributing to the phenotypic variance of SPTB: iv heritability (13.33%), dominance genetic (11.12%), maternal effect (15.23%), and individual environment (60.33%). These findings shed light on the architecture of SPTB pathogenesis and quantify the maternal and fetal contribution to SPTB. In Chapter 3, I perform an unbiased genome-wide association study for SPTB on 22 autosomal chromosomes. The data, which contain cases and controls collected by the Danish National Birth Cohort, were acquired from the National Center for Biotechnology Information Genotypes and Phenotypes Database. No SNP reached genome-wide significance. Although negative, the result provides proof of principle regarding the relatively low heritability of SPTB. Finally, I address insights learned from these analyses that may help guide future SPTB research and may be applicable to other human genetic studies. With these lessons, progress can be made in understanding the genetics of SPTB.