Even though a number of groups have identified peptidic inhibitors for DENV and WNV proteases, and several high throughput screening campaigns have been performed, the progress towards drug candidates has been very slow. This is in stark contrast to the related NS3/NS4A protease of HCV for which two peptidomimetic drugs were approved in 2011. In this review we will compare the NS3 proteases of the flaviviruses WNV and DENV with that of HCV, and answer the question whether the flavivirus proteases are inherently more challenging, or whether the lack of success is simply due to the limited resources that have so far been invested in these neglected disease targets.