Cancer cells usually reside in microenvironment stress, such as hypoxia, acidosis, Hypo-nutrition and Inflammation. In order to withstand the harsh microenvironment stress, cancer cells engage multiple evolutionarily conserved molecular responses to confer the ability to survive and proliferate. These responses to changes in microenvironment stress availability promote altered metabolism, called “metabolic reprogramming”, which has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. In addition, deregulated metabolism of glucose, glutamine and lipids under microenvironment stress have been identified to function as metabolic regulators in supporting cancer cell growth. Furthermore, extensive crosstalks are being revealed between the deregulated metabolic network and cancer cell signaling under microenvironment stress. These exciting advancements have inspired new novel strategies for treating various malignancies by targeting microenvironment factors. Here we review recent findings related to the regulation of microenvironment stress induced metabolic changes, and present future directions in this rapidly emerging area