Interpreting the biological implications of high-throughput experiments such as gene-expression studies, genome-wide association studies and large-scale sequencing studies is not trivial. Gene-set and pathway analyses are useful tools to support the interpretation of such experiments, but rely on curated pathways or gene sets. The recent development ofde novopathway discovery methods aims to overcome this limitation. This article provides an overview of the methods currently available and reviews the advantages and challenges of this approach. In detail, it highlights the particular issues ofde novopathway discovery based on genome-wide association studies data, for which multiple different strategies have been proposed.