This is a first in childhood leukemia multi-institutional pilot study investigating the combination of decitabine and vorinostat with chemotherapy for pediatric relapsed/refractory acute lymphoblastic leukemia (ALL). ALL is the most common leukemia in children with greater than 2,400 children diagnosed each year in the US. Although the majority of children with ALL achieve an initial remission, around 20% will later relapse with their disease. As the majority of children with relapsed ALL die of their leukemia, making relapsed ALL one of the leading causes of childhood cancer deaths, there is an urgent need to identify/incorporate new agents into upfront and relapse therapy to improve these poor outcomes. Our broad and long term objective is to eradicate relapse leukemia. This proposed clinical trial will investigate whether the combination of decitabine and vorinostat with chemotherapy can take the first step in eliminating relapsed ALL. The combination of decitabine with vorinostat is an encouraging approach to treating cancers and has been previously shown in adult studies to be synergistic in altering the neoplastic pathways of cancer cells and being well tolerated in human clinical trials. Decitabine is a demethylating agent that can reverse abnormal DNA methylation which is very common to a variety of human cancers including relapse ALL. Vorinostat restores DNA histone acetylation in cancer cells, and removal of these acetyl groups has been implicated in leukemia. Patients on this trial will receive 2 short pulses of decitabine and vorinostat beginning with decitabine on day 1, followed by vorinostat on day 3, and continue together through day 7. Chemotherapy with vincristine, prednisone, PEG-asparaginase and doxorubicin will begin on day 8. Decitabine and vorinostat will be restarted on day 15 and 17 respectively through day 21. Patients will have bone marrow samples sent for correlative studies at baseline, day 8 and day 22 as well as an end of therapy marrow (day 35) to evaluate response to treatment. The primary objective of this proposal is to characterize the toxicities of decitabine and vorinostat when used in combination prior to and concurrently with chemotherapy. Secondary objectives include determining end re-induction remission rates, including evaluation for minimal residual disease (MRD), as well as exploring the pharmacodynamic effects of decitabine and vorinostat in patients with relapsed/refractory ALL. The pharmacodynamic assays will assess the impact of decitabine and vorinostat on global and gene-specific promoter DNA methylation and histone acetylation, respectively, and will correlate the epigenetic changes with changes in gene expression. In addition, the functional impact of combined epigenetic therapy on in vitro chemosensitivity will be assessed. Finally, modulation of epigenetic profiles, gene expression signatures and chemosensitivity will be correlated with clinical responses in an effort to identify biomarkers predictive of clinical response.