Cancer stem cells(CSC) are a rare cell population within a tumor characterized by the ability to form tumors following injection into an immunocompromised host. While the role of CSC has been clearly established in animal models, evidence of their clinical relevance has been harder to demonstrate. A number of markers, or combination thereof, have been used to detect and measure, although non-specifically, CSC in almost all human tumors. Several pathways have been identified as crucial for, but not necessarily unique to, CSC survivaland proliferation, and novel agents have been designed to target such pathways. A number of such agents have entered early phase development. Further, drugs that have long been marketed for non-oncological indications have been redirected to oncology as they appear to affect one or more of such pathways. This article aims to review the available evidence on the clinical relevance of CSC from a drug development standpoint and the results of early phase clinical trials of agents interfering with the above pathways. It also discusses limitations of current clinical trial design and endpoints to demonstrate antiCSC activity as well as possible strategies to overcome these limitations.