Giardia duodenalis infects a wide array of hosts and is the most frequently reported human intestinal parasite. On an annual basis this parasite is responsible for~ 1 billion human infections of which> 200 million result in symptomatic disease. While infections are more prevalent in the developing world, this parasite is ubiquitous. Giardia infection can result in severe and chronic disease, causing malabsorption, weight loss and failure to thrive in children. There is also evidence that infection is linked to postinfection disorders including irritable bowel syndrome. Despite growing evidence of Giardia associated morbidity, current treatment options are inadequate. The frontline drug, metronidazole (MTZ), is associated with side-effects and drug resistance. It is also incredibly distasteful and must be taken in multiple doses over 5-7 days, factors which result in poor compliance, treatment failure, rapid re-infection and parasite resistance. In addition there is increasing evidence that MTZ has a collateral effect on host microbiome. To improve giardiasis treatment options in the long-term we recently screened compounds from the Compounds Australia Open Access Scaffold Library for anti-Giardia activity (2451 compound subset; 2/scaffold; Z-factor 0.75). Rational selection based on activity, novelty, and chemical liabilities identified three compound series with potent (IC50≤ 1μM) and selective activity for G. duodenalis. These compound series have been chosen as starting points for anti-Giardia drug development. The most promising compound identified to date is active against assemblage A, B and metronidazole resistant parasites (290-fold more potent than metronidazole) and has a Giardia vs human selectivity index of> 9000. Preliminary in vivo studies with this compound suggest no toxicity at up to 10X the calculated therapeutic dose and~ 75% efficacy at a dose of 0.7 mg/kg daily for 3 days. Further in vivo and activity studies with this compound and other lead series candidates are now under way and will be presented.