Somatic cells may be reprogrammed into pluripotent cells by the ectopic expression of defined transcription factors. However, some of the hurdles that affect the generation of induced pluripotent stem cells include extremely low efficiency and slow reprogramming. In the present study, we examined the effects of small molecules on cellular reprogramming and found that 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), an analog of cyclic adenosine monophosphate (cAMP), improves the reprogramming efficiency of reprogrammable mouse fibroblasts induced with dox in serum replacement (SR) medium. Interestingly, treatment with 8-Br-cAMP in mouse embryonic stem cell culture conditions does not affect reprogramming into the pluripotent state; however, reprogramming efficiency is significantly enhanced by inhibition of protein kinase A (PKA) in SR medium. Therefore, our results suggest that PKA signaling is unnecessary and may in fact act as a barrier to reprogramming into pluripotent stem cells.