Peroxisome proliferator-activated receptors (PPARs) regulate diverse biological processes such as development, differentiation, neoplastic conversion, inflammation and wound healing in addition to their critical roles in energy (lipid and carbohydrate) metabolism. Unliganded PPARs heterodimerize with retinoid X receptor alpha and repress transcription when bound to DNA by interacting with corepressor molecules. Upon canonical ligand binding, PPARs manifest conformational changes that facilitate the dissociation of corepressor molecules to enable a spatiotemporally orchestrated recruitment (association) of coactivators and coactivator-associated proteins to the liganded receptor. Functional significance for the existence of over 200 nuclear receptor cofactors is not readily evident, but emerging gene knockout mouse models show that some of the coactivators are essential for embryonic growth and survival and for controlling receptor specific target gene expression in a cell specific need based demands. Coactivators contain one or more highly conserved LXXLL amphiphatic alpha-helix motif, called nuclear receptor box, for direct interaction with the activation function 2 (AF-2) regions in nuclear receptors. PPARs interact with large multisubunit coactivator protein complexes, some exhibiting intrinsic histone acetyltransferase or methyltransferase activity, while others functioning as facilitators of ATP-dependent chromatin remodeling or as linkers to the basal transcription machinery. While the dynamic and coordinated changes in nuclear receptor expression and differences in the nature of their key target genes are important, it is becoming increasingly evident that perturbations in the expression of coactivators may affect the function of many nuclear receptors including PPARs. Tissue specific differences in coactivator expression add another dimension to the complexity of gene- and cell-specific transcriptional regulation. Identification of PPAR specific coactivators should further our understanding of the complexities of metabolic diseases associated with energy metabolism.