The desire to develop and evaluate drugs as potential countermeasures for biological and chemical threats requires test systems that can also substitute for the clinical trials normally crucial for drug development. Animal models have limited predictivity for drug efficacy, as is well known from many disappointments in clinical trials. Traditional in vitro and in silico approaches are not really game changers here, but the substantial investment into novel tools now underway might bring about a second generation of alternative approaches. The avenue pursued focuses primarily on the development of a Human on a Chip, i.e., the combination of different three-dimensional (stem) cell-based organ equivalents combined with microfluidics. The prospects of such approaches, their impact on the field of alternative approaches, and necessary complementary activities are discussed. The need to adapt quality assurance measures and experiences from validation is stressed.