The Sp/KLF family of proteins represents a group of 24 distinct transcription factors that modulate different morphogenetic pathways. In spite of the intensive biochemical characterization of Sp/KLF proteins, the study of their role in carcinogenesis is rather a nascent area of investigation. Thus, studies that focus on the cellular function of these proteins are of paramount importance for a more complete characterization of this evolutionarily conserved family of transcription factors. Consistent with this goal, the current study focuses on the functional characterization of the members of the Sp/KLF family of transcription factors that antagonizes the oncogenic function of KRAS. Because KRAS is mutated in more than 90% of pancreatic tumors the study of these proteins becomes of critical medical relevance. Using a combination of both transformation and cell growth assays we demonstrate that Sp5, Sp8, KLF1, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cell growth and suppress transformation mediated by oncogenic KRAS. A search for mechanisms underlying the growth and transformation suppressive functions of Sp/KLF proteins reveal that they mediate the downregulation of cyclin A2, B1 and D1. Reporter assay and chromatin immunoprecipitation assay shows that Sp/KLF proteins modulate the expression of these cyclins by regulating the transcriptional activity of their promoters. Expression arrays and PCR analysis revealed that the Sp/KLF genes with tumor suppressor activity have decreased expression in different type of tumors. Interestingly, the pancreas-enriched transcription factor KLF11 shows decreased expression in pancreatic cancer. Analysis of the potential mechanisms responsible of this downregulation demonstrated that the KLF11 promoter is aberrantly methylated in primary pancreatic tumors. 5-Aza-2 deoxycytidine treatment of the KLF11 methylated pancreatic cancer cell lines led to restoration of KLF11 expression. In addition, in vitro and in vivo studies show that KLF11 inhibits pancreatic neoplastic cell growth supporting a role for this gene in tumor suppression. In conclusion, we demonstrate that a subgroup of Sp/KLF proteins blocks neoplastic transformation mediated by KRAS. The antitumoral activity of Sp/KLF is associated suppression of cell growth regulation in pancreatic cancer cells. In addition, we identify KLF11 as tumor candidate for pancreatic cancer. Thus, together with other tumor suppressor e.g. DPC4/Smad4, KLF11 represents a novel potential drug targets in chemotherapeutic regimens aimed at reducing the oncogenic function of KRAS in pancreatic cancer. RU is supported by the Mayo Cancer Center and the National Institute of Health Grants DK52913 and CA102701.