Schematic of the experimental design approach. The input to the approach is a set of alternative representations of a gene-regulatory model, each of which is equally likely given current expression data. In the present work, the alternatives arise as a result of ambiguities in the regulatory roles of interactions in the model as inducers or repressors of downstream genes. Next, a scoring procedure is used to rank candidate perturbations according to their expected information gain over the model alternatives. High-ranking perturbations are applied to the system and characterized using gene-expression microarrays. The resulting expression profiles validate or invalidate particular connections in the model and reduce the set of model alternatives to those that are consistent with both old and new expression measurements.