Systems genomics has heralded not only the way we look at the variants but also the realm of precision medicine for identifying varied phenotypes and aberrations associated with the rare diseases. Anorectal Malformations (ARMs) are common congenital anomalies ranging with an incidence ratio of 1:1500 to 1:5000. In around 50% of individuals, this anomaly occurs as isolated ARMs while a remainder is found associated with other complex genetic syndromes. Recently, several genetic and molecular studies have been reported for such anomalies indicating the role of genetic factors influencing their etiopathogenesis. A paradigm shift has been observed for such malformations concentrating earlier on chromosomal aberrations to genomic alterations in form of single nucleotide variations (SNVs) and copy number variations (CNVs), suggesting the importance of factors altering the molecular pathways. Major developmental signaling pathway genes including Wnt, Fgf, Homeobox (Hox), Notch, Sonic Hedgehog (Shh), Gli2, CDX1, and Bmp4 were known to be affected in ARMs patients due to these genomic polymorphisms which could be targeted in future for precision drug therapies. In addition to this, we highlight the challenges to the existing systems genomics approaches and discuss how they contribute to understand the biology behind rare diseases including ARMs for improving disease management processes.