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Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS., Author Summary Cornelia de Lange Syndrome (CdLS) is a genetic disease marked by growth retardation, cognitive and neurological problems, and structural defects in many organ systems. The majority of CdLS cases are due to mutation of one copy of the Nipped B-like (NIPBL) gene, the product of which regulates a complex of chromosomal proteins called cohesin. How reduction of NIPBL function gives rise to pervasive developmental defects in CdLS is not understood, so a model of CdLS was developed by generating mice that carry one null allele of Nipbl. Developmental defects in these mice show remarkable similarity to those observed in individuals with CdLS, including small stature, craniofacial abnormalities, reduced body fat, behavioral disturbances, and high perinatal mortality. Molecular analysis of tissues and cells from Nipbl mutant mice provide the first evidence that the major role of Nipbl in the etiology of CdLS is to exert modest, but significant, effects on the expression of diverse sets of genes, some of which are located in characteristic arrangements along the DNA. Among affected genes is a set involved in the development of adipocytes, the cells that make and accumulate body fat, potentially explaining reductions in body fat accumulation commonly observed in individuals with CdLS.