With the current rate in growth of evidence in multiple sclerosis (MS) rehabilitation, systematic reviews and clinical guidelines typically lag behind the most currently published research findings. In addition, most health care professionals lack the time, resources, or adequate skills to identify and evaluate new evidence, and hands-on tools to implement the latest evidence into clinical practice are often lacking or not readily available. The Applying Evidence with Confidence (APPECO) platform is a newly developed online tool that addresses these key challenges. APPECO was initiated as a proof-of-concept for the common MS symptoms fatigue and cognitive function. Subsequently, intervention studies about depression, pain, and mobility were added. APPECO currently hosts detailed information from 250 randomized clinical trials, 293 interventions, and 1250 effect sizes on 53 patient outcomes. Few studies with high quality (ie, low risk of bias) are available specifically designed to test the benefits of MS rehabilitation on fatigue (n = 5 [2.4%]), cognitive function (n = 4 [1.6%]), and depression (n = 2 [0.8%]). No high-quality studies were included for pain and mobility. APPECO has the potential to address key challenges in evidence-based rehabilitation medicine for MS and to facilitate swift knowledge translation from evidence into clinical practice. Sustainability of APPECO depends on a continuous resource impulse (eg, financial, time, editorial management, platform maintenance) to ensure up-to-date information across all relevant MS symptoms and activity limitations (≈2-6 randomized controlled trials per month). Ways to optimize knowledge translation in the absence of high-quality evidence in APPECO need to be explored further.