Metal hyperaccumulation is a rare and fascinating phenomenon, whereby plants actively accumulate high concentrations of metal ions in their above-ground tissues. Enhanced uptake and root-to-shoot translocation of specific metal ions coupled with an increased capacity for detoxification and sequestration of these ions are thought to constitute the physiological basis of the hyperaccumulation phenotype. Nickel hyperaccumulators were the first to be discovered and are the most numerous, accounting for some seventy-five percent of all known hyperaccumulators. However, our understanding of the molecular basis of the physiological processes underpinning Ni hyperaccumulation has lagged behind that of Zn and Cd hyperaccumulation, in large part due to a lack of genomic resources for Ni hyperaccumulators. The advent of RNA-Seq technology, which allows both transcriptome assembly and profiling of global gene expression without the need for a reference genome, has offered a new route for the analysis of Ni hyperaccumulators, and several such studies have recently been reported. Here we review the current state of our understanding of the molecular basis of Ni hyperaccumulation in plants, with an emphasis on insights gained from recent RNA-Seq experiments, highlight commonalities and differences between Ni hyperaccumulators, and suggest potential future avenues of research in this field.