Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that has a multifactorial etiology. Despite having substantial genetic liability, <15% of the genetic contribution to NSCLP has been delineated. In our efforts to dissect the genetics of NSCLP, we found that variation in the CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) gene is associated with NSCLP and that the protein is expressed in the developing murine craniofacies. In addition, we found suggestive linkage of NSCLP (LOD > 1.0) to the chromosomal region on 8q13.2–21.13 that contains the CRISPLD1 gene. The protein products of both CRISPLD1 and CRISPLD2 contain more cysteine residues than comparably sized proteins. Interestingly, the folic acid pathway produces endogenous cysteines, and variation in genes in this pathway is associated with NSCLP. Based on these observations, we hypothesized that variation in CRISPLD1 contributes to NSCLP and that both CRISPLD genes interact with each other and genes in the folic acid pathway.