With recent approval of the minor groove binding agent trabectidin in Europe for the treatment of patients with soft tissue sarcomas, there has been renewed interest in minor groove binders. Though previously considered to be without clinical value due to their initial significant toxicities, new minor groove binders are emerging which are challenging that perception. Toxicities in the most recently completed and ongoing trials have been easily manageable. These agents have demonstrable anti-tumor activity against a wide variety of tumor types including leukemias, sarcomas, melanomas, breast and ovarian cancers. Applying these agents according to a particular tumor's context of vulnerability might reveal previously unconsidered applications for this diverse class of agents. This review provides a look at how minor groove binding agents have progressed from the lab through the clinic with particular emphasis on identifying the contexts of vulnerabilities of patient tumors which increase the effectiveness of these drugs.