Quantitative systems pharmacology (QSP) is a recent addition to the modeling and simulation toolbox for drug discovery and development and is based upon mathematical modeling of biophysical realistic biological processes in the disease area of interest. The combination of preclinical neurophysiology information with clinical data on pathology, imaging and clinical scales makes it a real translational tool. We will discuss the specific characteristics of QSP and where it differs from PK/PD modeling, such as the ability to provide support in target validation, clinical candidate selection and multi-target MedChem projects. In clinical development the approach can provide additional and unique evaluation of the effect of comedications, genotypes and disease states (patient populations) even before the initiation of actual trials. A powerful property is the ability to perform failure analysis. By giving examples from the CNS R&D field in schizophrenia and Alzheimer's disease, we will illustrate how this approach can make a difference for CNS R&D projects.