Cancer stem cells can differentiate and self-renew. Therefore, they are resistant to traditional therapies and cause cancer relapse. The most determinant factor for the CSCs resistance is the tumor microenvironment, which contains many aspects to prevent CSCs from being eradicated. In this review, we will introduce different aspects according to the tumor microenvironment (TME) like hypoxia, which allows CSCs to flourish in the TME; CAF, which contributes to the self-renewal quality of CSCs; immune cells, which could potentially incapacitate cancer cells and decrease the stemness of CSCs, and different major signaling pathways that help with the proliferation and survival of CSCs. We also conclude with the major clinical trials involved in each of the signaling pathways, which presents possibilities to assist with therapy..