The peroxisome proliferator-activated receptor ¿ (PPAR¿) is a key regulator of terminal adipocyte differentiation. PPARd is expressed in preadipocytes, but the importance of this PPAR subtype in adipogenesis has been a matter of debate. Here we present a critical evaluation of the role of PPARd in adipocyte differentiation. We demonstrate that treatment of NIH-3T3 fibroblasts overexpressing PPARd with standard adipogenic inducers led to induction of PPAR¿2 expression and terminal adipocyte differentiation in a manner that was strictly dependent on simultaneous administration of a PPARd ligand and methylisobutylxanthine (MIX) or other cAMP elevating agents. We further show that ligands and MIX synergistically stimulated PPARd-mediated transactivation. In 3T3-L1 preadipocytes, simultaneous administration of a PPARd-selective ligand and MIX significantly enhanced the early expression of PPAR¿ and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation. Finally, we provide evidence that synergistic activation of PPARd promotes mitotic clonal expansion in 3T3-L1 cells with or without forced expression of PPARd. In conclusion, our results suggest that PPARd may play a role in the proliferation of adipocyte precursor cells, whereas activation of endogenous PPARd in 3T3-L1 cells appears to have only minor impact on the processes leading to terminal adipocyte differentiation.