Currently available drugs for Chagas' disease are limited by toxicity and low efficacy in the chronic stage. Posaconazole, the most advanced new anti-chagasic drug candidate, did not fully confirm its initial potential in a Phase II clinical trial for chronic Chagas' disease. Given that posaconazole is highly active against Trypanosoma cruzi in vitro, and was very well tolerated in clinical trials, it should not be abandoned. Rather, a combination therapy may provide a highly promising outlook. Systems-scale approaches facilitate the hunt for a combination partner for posaconazole, which acts by blocking sterol biosynthesis. Mounting evidence suggests the functional interactions between sterols and sphingolipids in vivo. Here, we propose combining sterol and sphingolipid biosynthesis inhibitors to advance drug development in Chagas' disease.