The capacity to generate disease-relevant cell populations from human pluripotent stem cells has tremendous potential for shedding light on human disease mechanisms. I will discuss basic principles of in vitro disease modelling, including the generation of isogenic models with CRISPR/Cas9, the issue of recurrent culture-acquired mutations and how to assess stem cell genomic integrity, and cell type maturity and phenotyping strategies. To frame these issues, I will discuss my research group's interest in obesity, which is largely a disease of excess food intake, which is in turn regulated by neurons in the hypothalamus. We use human stem cell-derived hypothalamic neurons to gain insight into the environmental and genetic factors that alter neuron function.