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In the era of network biology, understanding the complexity of the signaling pathways network in cancer origin, progression and metastasis will dramatically alter and improve treatment strategies. Prognosis of gastric cancer remains poor. Clinical decisions on treatment are based on tumor-node-metastasis (TNM) staging, but are suboptimal. This perspective review, integrating several concepts, including cancer stem cells, provides a novel treatment model for tailoring the best treatment in individual patients with gastric cancer. Biologic metastatic steps (invasion, angiogenesis, intra/extravasation, colonization and microenvironment at distant organs) are orchestrated by mutated genes. Identifying and profiling these key genes and their interactions with environmental factors such as Helicobacter pylori, driver mutations and interacting signaling pathways using high-throughput technologies (including omics, resequencing, genome-wide associations studies and RNAi) in unbiased studies can lead to the development of both novel biomarkers and targeted agents. A comprehensive bench-to-bedside treatment-guided algorithm is provided for optimum preoperative or postoperative combination of cytotoxic and targeted agents. The protocol can be applied with adequate modification for most solid tumors.