Systems Biology is the quantitative analysis of dynamic interactions among several components of a biochemical system, aiming at an understanding of the behavior of the system as a whole. From an experimental perspective, systems biology is a suitable tool to support the biologist in the process of hypotheses generation and the efficient design of experiments. In this chapter, we discuss the elements of a systems biology methodology based on the interaction between experimental biologists and theoreticians. We, furthermore, show the use of such a methodology in a case study, analyzing receptor and transcription factor modulation affecting the responsiveness of the JAK2/STAT5 pathway.