The prevalence and incidence of Parkinson’s disease (PD) is increasing due to a prolonged life expectancy in our modern societies. This highlights the need for a better understanding of the pathological mechanisms and new therapeutic approaches. However, traditional cell and animal models to study PD are suboptimal, thus limiting the development of the field. Nowadays, PD modeling with induced pluripotent stem cells (iPSCs) is facilitated by high-efficiency neural-specific differentiation protocols and the possibility to correct or induce mutations and create marker cell lines using designer nucleases that can cut at specific sites of the genome. Here, we knocked-out the three PD related genes PINK1, PARK2 and PARK7 in an iPSC clone from a healthy person using zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs), creating six different knock-out cell lines sharing the same genetic background. These iPSCs were differentiated into cortical and dopaminergic neurons and exposed to different cellular stressors, finding an impairment of cell viability in the knock-out neurons compared with wild type and an increment in Caspase 3 activation that triggers the cell death. We also showed that the sensitivity to drugs is directly related with PINK1, PARK2 and PARK7 dysfunction by overexpressing wild type version of the genes in knock-out neurons. Finally, treatment with antioxidants and the analysis of GSH/GSSG ratio revealed that an impairment in cellular antioxidant systems is responsible for cell death in the knock-out cortical neurons. In this project, we demonstrate the utility of iPSCs engineered with designer nucleases to generate a state-of-the-art model for PD and so understand better the pathogenesis of the disease.