When I moved to UCSD, we began the Alliance for Cellular Signaling and our initial focus was B- and T-lymphocytes. Very soon, it became obvious that B-cells cannot be transfected easily and perturbation experiments were not an option. We shifted to studying a macrophage cell line, the RAW 264.7. This cell, which is a great model system for studying inflammation, became our mammalian systems biology learning playground for several years. We first used the phosphoproteomic and cytokine measurements using a multitude of ligands acting on the macrophages and developed a suite of novel computational methods. These methods led to very interesting biological insights. We mapped the common and distinct signaling pathways in macrophages, investigated the transcriptional response that were end points of the signaling cascade. Several papers resulted from this “learning experience” both in terms of methods development and mechanistic biology. Lipidmaps was initiated a few years after the Cell Signaling Project and the logical choice for the model system to study lipidomics was again the macrophage cell. Macrophages while being cytokine factories were also involved in physiological lipid changes especially in producing lipid mediators of pain and inflammation. The connection with atherosclerosis and insulin resistance was also an important factor in this choice. Given the mass spectrometric expertise in the consortium and the ever-improving transcriptomics methods, we were able to map completely the cellular lipidome in macrophage activation. We published the first mammalian lipidome paper and along with it came a host of statistical methodology that we developed to analyze integratively the transcriptome and the lipidome.