Chemokines are important regulators of directional cell migration and tumor metastasis. A genome-wide transcriptome array designed to uncover novel genes silenced by methylation in lung cancer identified the CXC-subfamily of chemokines. Expression of 11 of the 16 known human CXC-chemokines was increased in lung adenocarcinoma cell lines after treatment with 5-aza-2'-deoxycytidine (DAC). Tumor-specific methylation leading to silencing of CXCL5, 12 and 14 was found in over 75% of primary lung adenocarcinomas and DAC treatment restored the expression of each of the silenced gene. Forced expression of CXCL14 in H23 cells, where this gene is silenced by methylation, increased cell death in vitro and dramatically reduced the in vivo growth of lung tumor xenografts through necrosis of up to 90% of the tumor mass. CXCL14 re-expression had a profound effect on the genome altering the transcription of over 1000 genes, including increased expression of 30 cell-cycle inhibitor and pro-apoptosis genes. In addition, CXCL14 methylation in sputum from asymptomatic early-stage lung cancer cases was associated with a 2.9-fold elevated risk for this disease compared with controls, substantiating its potential as a biomarker for early detection of lung cancer. Together, these findings identify CXCL14 as an important tumor suppressor gene epigenetically silenced during lung carcinogenesis.