Recent analyses revealed that Krüppel-like factors (KLFs) play important roles in both normal development and carcinogenesis. Of the 16 known KLFs, KLF4 has been shown to be involved in the regulation of proliferation, differentiation and tumorigenesis of gastrointestinal tract epithelium. Clinical, experimental and mechanistic findings indicate that KLF4 is a bona fide tumor suppressor for both gastric and colorectal cancers. In this review, we summarize how this growing area of research has formed and the challenging new frontiers for better understanding of the oncogenic potential of the KLFs.