Immune responses rely on the dynamic coordination of diverse immune cell types. Each immune cell must sense and respond appropriately to signals while integrating information about the tissue context. Immune cells communicate with each other and with tissue cells enabling coordination at the physiological scale. Defective or over-active dysregulation of immune signaling processes underlie a majority human pathologies. Recent technological advances of next gen sequencing and mass spectrometry characterize top-down Systems Immunology approaches that enable statistical inference of signaling events within and between cells, and in space. At the same time, bottom-up systems biology approaches of Immune Signaling that leverage molecular mechanisms knowledge have advanced to dissect the non-linear and time-resolved dynamic interplay between molecular pathways and cells. This Keystone Symposia meeting offers a timely opportunity to explore the synergies between two complementary approaches that have made rapid progress in recent years: top-down Systems Immunology and bottom-up Systems Biology or Immune Signaling. Speakers will exemplify different approaches to study diverse physiological and pathological phenomena at different scales, thereby leading to the kind of cross-pollination and spirited discussions that inform future research.