Among the major unmet needs in the MS field is defining the biological mechanisms that underlie patient heterogeneity – whether elucidating what contributes to the highly variable clinical course observed across patients, or how to guide optimal treatment selection and decisions around staying the course, switching, or even discontinuing immune therapy in individual patients. A major advance in precision immunology would be the ability to measure an individuals immune state – including the capacity to define and distinguish normal immune health from immune ill-health – thereby identifying predominant immune imbalances and better-tailored treatment. In tandem with the remarkable growth in available immune therapies (and, in part, driven by their development – including important lessons from both their successes and failures), we have extended our understanding of the complex cellular ‘immune interactions, checks and balances’ involved in MS immune pathophysiology. ‘Perturbing’ the complex and incompletely understood disease mechanisms with a therapeutic, together with careful measurements in high-quality samples that assess both phenotype and function of immune cells and their interactions, and relating such measurements to clinical and imaging outcomes of well-characterized patient cohorts, can then inform on both the mode-of-action of the therapy in development, but also provide insights into the disease relevant mechanisms themselves. Vaccination, another form of standard immune perturbation, can be similarly harnessed to characterize the heterogenous immune response propensities across individuals, and also provide novel insights into the complex in vivo interactions of the immune cell subsets involved in maintenance (or restoration) of normal immune checks and balances.