Cleft lip and/or palate (CL/P) is a highly prevalent craniofacial deformation worldwide, that is challenging to treat. Despite the series of reconstructive surgeries, orthodontic treatments, and functional rehabilitation therapies, patients can not fully recover from the esthetic and functional defect they were born with. A paradigm-shift in treatment approach is needed to lift the medical, psychosocial, and financial burdens from the patients and their families, one that would intercept the malformation in utero and recapitulate normal development of the lip and the palate before birth. A necessary first step towards this goal is to decipher the intricate molecular mechanisms underlying CL/P pathogenesis. We used a novel double transgenic mouse model Esrp1-/-;Sox2+/- and RNA-sequencing technology to search for target genes responsible for CL/P. The ablation of Esrp1 results in orofacial clefting in mouse embryos, but Sox2 haploinsufficiency in Esrp1-/- mouse rescues the CL/P phenotype by restoring normal development of the face. The analysis of the transcriptomic variations between Wild Type, Esrp1-/- and Esrp1-/-;Sox2+/- mice revealed that numerous genes were differentially expressed in the ectoderm and mesenchyme of the facial prominences at a critical stage for fusion. Among the genes that were either normalized or compensated by Sox2 haploinsufficiency in the Rescue model, we identified genes from known signaling pathways like Bmp4 and key epithelial-mesenchymal transition genes such as Snai1, Twist1, and Zeb1. This preliminary study lays the groundwork for promising treatment opportunities for orofacial clefting.