Breast cancer is the leading incident of cancer and the second-leading cause of cancer-related deaths in women with the majority dying from metastatic disease. Previous studies have demonstrated the importance of inherited polymorphisms in the progression of breast cancer metastasis. In this study, we used a mouse cross between the metastatic mammary tumor model MMTV-PyMT and MOLF/EiJ to identify the circadian transcription factor Arntl2 as a metastasis modifier in estrogen receptor (ER)-negative breast cancer. Sequence analysis of MOLF/EiJ demonstrated that non-synonomous substitutions of Arntl2 existed between MOLF/EiJ and MMTV-PyMT mice. However, modulation of expression levels of Arntl2 signifcantly affected metastastic capacity in multiple mammary tumor cell lines indicating that transcriptional levels play an important role in metastatic progression. Furthermore, implantation of wild type tumor cells into Arntl2 knockout mice demosntrated that the effect of Arntl2 on metastasis is a tumor cell intrinsic phenotype. To identify putative causative eQTL variants that modulate Arntl2 expression levels DNase hypersensitivity site (DHS) analysis was performed. This analysis revealed 13 single nucleotide polymorphisms (SNP) in the proximal promoter region that potentially affect transcriptional activity. CRISPR/Cas9-mediated substitution of the MOLF/EiJ polymorphic promoter allele reduced Arntl2 expression and metastatic capacity of the 4T1 metastatic mammary tumor cell line, as predicted. Taken in toto, these results provide strong evidence that the expression levels of the circadian rhythm gene Arntl2 plays an important role in the predisposition to the development of mammary tumor pulmonary metastases.