Glucose, glutamine and molecular oxygen are fundamental for tumor cell survival and proliferation.Active proliferation of tumor cells increases the demand for those basic nutrients to produce energy and building blocks.The supplies of these nutrients to tumors, however, are often limited by the microenvironment associated with tumors.While the mechanisms underlying the oxygen sensing and adaptive responses of cells to hypoxia have been well elucidated,how tumor cells monitor the glucose and glutamine supply remain unclear.Using systemic biology approaches, we have studied the gene expression reprogramming upon glucose and glutamine starvation.Based on analysis of the functional interaction between transcriptional regulators and their target genes, potential transcriptional regulators involved in the gene expression reprogramming have been predicted.Next, based on functional interactions among multiple genes that were co-regulated, we have attempted to decipher the sensing mechanisms, signal transduction pathways and eventual metabolic responses.Based on our data and analyses, we will present a general model to explain the special features of cancer metabolism and tumors cells response to the nutrient insufficiency.A better understanding of the molecular mechanisms underlying the nutrient sensing, signaling pathways, subsequent cell stresses and cells eventual responses will pave a way to the development of novel therapy for cancers.