Abstract: Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency genes. Functional analysis indicates Kdm3b, an H3K9me1/2 demethylase, and the DNA demethylation enzymes Tet1 and Tet2, to be critical for AA+2i effects. Temporally, Kdm3b was essential early while Tet enzymes were required throughout the conversion. In order to evaluate the requirement of Kdm3b on Tet function, we performed 5hmC enrichment analysis on reprogramming intermediates depleted of Kdm3b. Interestingly, we found that Kdm3b was required for resolving 5hmC at certain gene promoters that are associated with stem cell function. Furthermore, the mis-processing of 5hmC within a subset of genes had decreased expression upon Kdm3b depletion. Collectively, our data provides insight into the epigenetic cross talk during the late stages of reprogramming.