Systems Genetics approaches, in particular those relying on genetical genomics data, put forward a new paradigm of large-scale genome and network analysis. These methods use naturally occurring multi-factorial perturbations (e.g. polymorphisms) in properly controlled and screened genetic crosses to elucidate causal relationships in biological networks. However, although genetical genomics data contain rich information, a clear dissection of causes and effects as required for reconstructing gene regulatory networks is not easily possible.