ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) is a member of the ARF family of the Ras superfamily of small GTPases that are known to be involved in multiple regulatory pathways altered in human carcinogenesis. Here, we review recent work that has provided insights into the role of this small gene as an emerging player in both familial and sporadic cancers of several histotypes. ARLTS1 is a low penetrance gene that is primarily dysregulated in sporadic lung cancer by promoter hypermethylation. Two ARLTS1 polymorphisms are also associated with familial cancer risk. Down-regulation of ARLTS1 is seen in all lung cancer cell lines studied and in a significant proportion (37%) of primary lung tumors. Restoration of ARLTS1 expression in ARLTS1-deficient lung cancer cell lines by either demethylation or adenoviral transduction leads to apoptosis via caspase-dependent mechanisms. Furthermore, ARLTS1 re-expression induces an in vivo decreased tumor growth in preclinical models of lung cancer. Microarray analysis of gene expression patterns in cells transduced with ARLTS1 demonstrates that various pathways involved in cell survival, proliferation and development mediate its pro-apoptotic effects.