In the context of efficacy testing of pharmacological compounds in animal models, replacement of some of these models with a relevant human in vitro system appears attractive, in particular with regard to large scale screening. Here, we show results from initial phases of a project, which attempts to explore the outstanding potential of human embryonic stem cell (hESC)-based in vitro models with special regard to neuronal stress as a potential replacement of animal models for human neurodegenerative diseases. We show the functionality of neurons derived from hESC precursors by calcium imaging, mitochondrial potential measurements and Western blots and moreover demonstrate that this model reproduces crucial mechanistic aspects observed during ischemia and excitotoxicity that are thought to be at the core of some neurodegenerative diseases. Also, the broader possibilities for refining surrogate molecular information emerging from the detailed analysis of this model are discussed.