Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs’ unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs’ unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways’ ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFβ (transforming growth factor-β)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.