Untargeted strategies have changed the rules of the game in complex mixture analysis, introducing an amazing potential for medical and biological applications that is just starting to be tapped. But with great power come great challenges; although untargeted mixture analysis opens the road for many exciting possibilities, the road is still full of perils. On the one hand, this article highlights some of the difficulties that need to be sorted for mixture analysis by NMR to fulfill its potential, along with insight on how they may be managed. Highlighted key points include the need for 'computer friendly' solutions for sharing data, experimental design and algorithm to facilitate the steady growth of knowledge and modeling ability in the field, and the need for large-scale studies to improve confidence in newly identified biomarkers. On the other hand, the second part of this article presents some breakthroughs in NMR experiments that, when combined, may modify the landscape of mixture analysis. Copyright © 2016 John Wiley & Sons, Ltd.