Multi-modal monitoring has become an integral part of neurointensive care. However, our approach is at this time neither standardized nor backed by data from randomized controlled trials. The goal of the second Neurocritical Care Research Conference was to discuss research priorities in multi-modal monitoring, what research tools are available, as well as the latest advances in clinical trial design. This section of the meeting was focused on how such a trial should be designed so as to maximize yield and avoid mistakes of the past.