Resistance to therapy is a major hurdle in current cancer treatments. A major part of the problem is heterogeneity. Tumors, by their nature, have multiple cell lineages with varying characteristics. Among these are cancer stem cells (CSCs). CSCs can regenerate a tumor even after treatment kills many of its other cells. And they can go dormant, transport drugs outside the cell membrane, avoid apoptosis, and express resistance-conferring non-coding RNAs, all of which boost tumors’ resistance to treatment. A new review describes common CSC surface markers, deregulated signaling pathways, and resistance mechanisms as well as the status of research into CSC therapies. Current therapies targeting CSCs do not address tumor heterogeneity or the complexity of the tumor microenvironment. Further research into these pathways may yield novel therapies, including combination treatments that attack multiple CSC pathways along with actively proliferating tumor cells yielding more successful ways to target treatment-resistant tumors.