Systems pharmacology is becoming a key tool for biotherapeutics drug discovery and development. Systems pharmacology utilizes mathematical models that describe the pharmacokinetics and pharmacodynamics (PK/PD) on a mechanistic level taking into account the relevant physiology. These models are used along the entire drug discovery and development process for hypothesis building, prediction, data integration and data analysis enabling informed decision making on a quantitative and mechanistic basis. The use of systems pharmacology can be seen as a natural consequence of the current trend developing biotherapeutics with increasingly complex mode of actions. For these cases, which include for example bi-specific antibodies or antibody-drug conjugates, the PK/PD relationship is dependent on many factors with implications for modality selection, candidate screening and selection, toxicology studies, first in human dose selection and for dose finding. Systems pharmacology can capture the complexity and dependencies to provide an early understanding of the PK/PD relationship, to design an appropriate preclinical strategy and to assess early of how the PK/PD relationship could translate to patients. Application of systems pharmacology within a drug discovery and development context not only requires a solid scientific basis; the right talent, organizational structure and computational tools must be available as well in order to contribute to the clinical success of novel biotherapeutic candidates.