Cancer stem cells (CSCs) are a rare subpopulation of tumor cells with stemness properties (capable of self-renewal and differentiate into different lineages) and with increased genomic instability-bearing cells. These cells are considered the driver of tumor initiation and progression, along with the capacity to colonize at distant sites. CSCs are also associated with therapy resistance and relapse of the disease in patients with cancer. In addition, during the time of tumor evolution, CSCs generate various types of clones with different phenotypic features and molecular makeups, thereby creating heterogeneity of tumors. A higher degree of plasticity of CSCs allows them to undergo dormancy during therapeutic insults, whereas they become reactivating cancer cells followed by reprogramming the cancer cells after the therapeutic regimens, thereby cancer recurrence. Therefore, CSCs are responsible for most of the hallmarks of cancer and contribute significantly to cancer-related mortality in patients with cancer. Thus, in this chapter, we discuss the roles of CSCs in cancer pathogenesis, which could shed better insights into developing effective therapeutic strategies against CSCs.