Colorectal cancer (CRC) is among the most commonly diagnosed and lethal cancers worldwide. CRC is a multistep process that requires the addition of several genetic and epigenetic aberrations, which result in the progressive malignant transformation of normal cells into the colonic mucosa leading to cell proliferation and metastasis. The most studied hallmarks of carcinogenesis colorectal are the unlimited replicative potential of stem cells and the reprogramming of metabolic pathways. These characteristics have been utilized several years ago for development of therapeutic treatments for CRC. Treatment of solid tumor cancers as CRC has been varying due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. The microenvironment maintaining the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia provides the necessary conditions for proliferative growth of cancer stem-like cells. These cells are responsible for the therapy resistance and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy with monoclonal antibodies against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients; however, such treatments are not completely curative and a large proportion of tumors retains chemoresistance or show recurrence. Recently, others mechanism as inflammation and participation of cellular metabolism has been related in the cancer progression. This chapter reviews the current knowledge regarding the molecular phenotype of CRC cells and discusses the mechanisms contributing to their maintenance.