Huntington’s Disease (HD) is a neurodegenerative disorder characterised by selective loss of medium spiny neurons (MSNs) from the striatum, resulting in a decline in motor control and behavioral disinhibition. Currently, besides palliative care, there are no treatmnets which alter either the onset or the course of this devestating, terminal illness. HD is remarkable in that it is genetic disorder affecting a single exon in an identified gene to produce a predictable glutamine expansion (polyQ) in a known protein (huntingtin, Htt), yet we still do not know with any certainty the causal link between the polyQ expansion in mutant Htt and the selective death of MSNs in the striatum (Zuccato et al., 2010). Although transgenic models have provided most of the information which is currently known about the pathophysiology of HD, hallmarks of the human disease are often manifest either poorly or late in transgenic rodents. Thus, to address fundemental questions about the roles of mtHtt in the human disease, we have used induced pluripotent stem cells (iPSC) from HD patients with polyQ expansions of 33, 60, 109 and 180 (The HD-IPSC Consortium., 2012; Ebert et al., 2013), and differentiated them using a novel protocol which accelerates differentiation and synaptogenesis, such that cells demonstrate functional and synaptic marker profiles characteristic of mature central neurons within 21 days of plating (Rushton et al., 2013). Remarkably, these pateint-derived neurons show many of the polyQ-dependent disease phenotypes, including differential and BDNF-dependent glutamate-induced neuronal excitotoxicity, calcium dyshomeostais, caspase activation, and mitochondrial dysfunction, which characteriste HD. Recently, this rapid maturation system has been applied to hydrogel-supported, 3-D cultures of iPSC-derived neurons and the allelic sequence has been enhanced to include more disease-relevant polyQs, from 38 to 50. The challenge now is to translate this highly tractable disease model to high-throughput platforms in order to dentify small molecules which can rescue these dissease-appropriate phenotypes, paving the way for rational design of novel therapeutic interventions.