The intestinal protozoan parasites pose serious health concerns, infecting more than one billion individuals every year and mainly causing diarrhea in infants and adults. Main pathogens include Giardia intestinalis, Entamoeba histolytica, Cyclospora cayetanensis, and Cryptosporidium spp. causing giardiasis, amoebiasis, cyclosporiasis, and cryptosporidiosis, respectively. The drug arsenal to treat these diseases is limited (<25 drugs are in clinical use) for the treatment of all protozoal infections. The existing treatment options are decades of years old (discovered in 1930–1980s) and have limitations such as low therapeutic index, toxic side effects during long-term treatment, and drug resistance. Therefore, urgent renewed drug discovery efforts are needed to tackle these neglected protozoal diseases. This chapter discusses the current status of treatment options and their limitations, along with current drug discovery efforts. We conclude that the knowledge gained in the genomic and post-genomic era should be appropriately harnessed to accelerate the futuristic drug discovery process in this field.