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The past 10 years have seen remarkable progress in the research, diagnosis, and therapy of gastrointestinal cancer. It has been shown that the development, invasion and metastasis of gastric and colorectal cancers require multi-step cascading process in the complex interaction between cancer cells and stromal cells in tumor microenvironment. This special issue, “Cancer-Stromal Interaction in Gastrointestinal Cancer” brings together the most recent information on carcinogenesis, biology, stem cells, progression, angiogenesis, productive fibrosis, and roles of microRNAs in tumor invasion of gastrointestinal cancer, with contribution by renowned researchers. Better understanding of these events will no doubt provide new approaches for biomarkers of diagnosis and effective therapeutic targeting of gastrointestinal cancer.