Safe, effective and affordable orally active therapies for trypanosomiasis capable of overcoming resistance are required, so the identification of new anti-trypanosomal drug candidates is an urgent priority. Compared to the last 15 years there has been a revival of drug research and development regarding neglected parasitic diseases, and a number of drug development projects are currently ongoing [11] . In view of this, the researchers have endeavored to compile in the present section of the review, diverse series of compounds that have been recently synthesized by various research groups targeting DNA minor groove and many other new targets. Based on the mechanism of action this section has been divided into two sub-sections. The first sub-section includes the series of compounds acting as DNA minor groove binders while in the second sub-section are included all the other anti-trypanosomal compounds and their respective targets. Also are described herein prodrug approaches to provide oral bioavailability for the dication class.