We previously reported that mice deficient in stearoyl-CoA desaturase-1 (Scd1) and maintained on a very low-fat (VLF) diet for 10 days developed severe loss of body weight, hypoglycemia, hypercholesterolemia, and many cholestasis-like phenotypes. To better understand the metabolic changes associated with these phenotypes, we performed microarray analysis of hepatic gene expression in chow- and VLF-fed female Scd1^+/+ and Scd1^-/- mice. We identified an extraordinary number of differentially expressed genes (>4000 probe sets) in the VLF Scd1^-/- relative to both VLF Scd1^+/+ and chow Scd1^-/- mice. Transcript levels were reduced for genes involved in detoxification and several facets of fatty acid metabolism including biosynthesis, elongation, desaturation, oxidation, transport, and ketogenesis. This pattern is attributable to the decreased mRNA abundance of several genes encoding key metabolism transcription factors, including LXR, RXR, FXR, PPAR, PGC-1, SREBP1c, ChREBP, CAR, DBP, TEF, and HLF. A robust induction of endoplasmic reticulum (ER) stress is indicated by enhanced splicing of XBP1, increased expression of the stress-induced transcription factors CHOP and ATF3, and elevated expression of several genes involved in the integrated stress and unfolded protein response pathways. The gene expression profile is also consistent with induction of an acute inflammatory response and macrophage recruitment. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining metabolic homeostasis in the absence of sufficient dietary unsaturated fat and point to a novel cellular nutrient-sensing mechanism linking fatty acid availability and/or composition to the ER stress response.