Gastrointestinal (GI) tract cancers account for a significant proportion of human malignancies. While classical multistep carcinogenesis is characterized by the stochastic accumulation of genetic mutations, additional extrinsic factors can also contribute to tumor promotion. Inflammation plays a critical role in cancers of the GI tract, for which the two major etiological factors are tissue injuries and altered microbiota. Together with infiltrating immune cells, all of these components generate a dynamic tumor microenvironment that inevitably induces malignant progression and metastatic growth. Crosstalk between tumor and immune cells is mediated by a multitude of pro- and anti- inflammatory cytokines. Their biological actions are propagated in both tumor and immune cells through an intricate network of intracellular signaling pathways that ultimately modulate essential cellular functions such as tumorigenic properties and lineage specification. Using the vast amount of information stored in the database on genetic changes associated with human cancers that has been collected over the past decades, this book chapter will first profile the genomic and transcriptomic landscapes of some of the major GI tract cancers. Critical driver genes and pro-inflammatory cytokines will be discussed in detail. The mechanisms by which genetic mutations in cancer cells can provoke inflammation and vice versa will be explored. The way in which the symbiotic relationship between cancer cells and chronic inflammation can modulate tumor cell behavior will be examined. We will present some of the most recent advancements in the targeting of inflammation for the treatment of GI tract cancers.