Our purpose is to investigate the impact of circadian and melatonin pathway genes as well as their interactions with night-shift work (NSW) on breast cancer risk in Korean women. Information about NSW and other covariates was collected using a structured questionnaire and twenty-two polymorphisms in 11 genes were analyzed in a hospital-based case-control study with 941 cases of breast cancer and 959 controls. In analysis of the main effects of each single nucleotide polymorphisms(SNPs), variants in CLOCK rs11133373 was associated with breast cancer risk even after false discovery rate (FDR) correction (Odd Ratios (OR) = 1.38 (95% Confident Interval (CI) 1.14-1.69) in CG and CC compared to GG genotype. Analysis of MTNR1A rs2119882 demonstrated a decreased risk of breast cancer in CC compared to TT (p-FDR = 0.043). A correlation between NSW and breast cancer interaction was found in two loci. NSW increased risk of breast cancer in women who carried the heterozygote genotype of CRY2 rs2292912 (OR = 1.98, 95% CI = 1.14-3.44) or carried at least one minor allele of RORA rs1482057 (OR = 2.20, 95% CI = 1.10-4.37). Our study results support a putative role for several loci of circadian genes and genes of melatonin biosynthesis and their interaction, and the gene interactions with NSW in the development of breast cancer.