Human induced pluripotent stem cells (hiPSCs) derived from patients are increasingly being used to study disease-relevant phenotypes in vitro. Although this approach has created valuable insights into illnesses with rapid and robust manifestations, such as heart disease or muscular atrophy, diseases with long latency and slow progression are more difficult to study. The subtle in vitro phenotypes of stem-cell models of diseases, such as Parkinson's or Alzheimer's, are easily missed when patient-derived cells are compared with cells from genetically different healthy controls. To overcome this problem, Soldner et al. used pairs of isogenic stem cells that differed only in a specific mutation that confers susceptibility to Parkinson's disease. Using zinc-finger nucleases, the authors engineered such cells by either introducing point mutations in the α-synuclein gene of embryonic stem cells derived from healthy individuals or correcting a mutation in hiPSCs from patients with Parkinson's. They showed that differences in gene expression between cells of different genetic backgrounds are larger than those caused by genome editing. (Cell 146, 318–331, 2011)