There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.