Selective peroxisome proliferator-activated receptor γ (PPARγ) modulators (SPPARγMs) have been actively pursued as the next generation of insulin-sensitizing antidiabetic drugs, because the currently marketed PPARγ full agonists, pioglitazone and rosiglitazone, have been reported to produce serious adverse effects among patients with type 2 diabetes mellitus. We conducted extensive transcriptome profiling studies to characterize and to contrast the activities of 70 SPPARγMs and seven PPARγ full agonists. In both 3T3-L1 adipocytes and adipose tissue from db/db mice, the SPPARγMs generated attenuated and selective gene-regulatory responses, in comparison with full agonists. More importantly, SPPARγMs regulated the expression of antidiabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, whereas PPARγ full agonists regulated both gene sets proportionally. Such SPPARγM selectivity demonstrates that PPARγ ligand regulation of gene expression can be fine-tuned, and not just turned on and off, to achieve precise control of complex cellular and physiological functions. It also provides a potential molecular basis for the superior therapeutic window previously observed with SPPARγMs versus full agonists. On the basis of our profiling results, we introduce two novel, gene expression-based scores, the γ activation index and the selectivity index, to aid in the detection and characterization of novel SPPARγMs. These studies provide new insights into the gene-regulatory activity of SPPARγMs as well as novel quantitative indices to facilitate the identification of PPARγ ligands with robust insulin-sensitizing activity and improved tolerance among patients with type 2 diabetes, compared with presently available PPARγ agonist drugs.