Background and Purpose Stroke represents one of the most important causes of morbidity and mortality worldwide. Innovative systems biology-based approach is likely to increase the understanding of the underpinning of acute stroke promise to enhance stroke prevention, acute treatment, and neurorehabilitation. Recent growing body of evidence with shared pathobiology with COVID-19 and the critically important role of inflammation in the context of stroke points to far-reaching consequences of acute stroke, just as in the case of COVID-19. So far, stroke typically (...) defined by late-appearing disease manifestation by the range of stroke subtypes as defined by the WHO or American Stroke Association. This definition neglects the underlying pathobiological mechanisms such as low-grade chronic inflammation and already compromised vascular system. Diseases such as stroke is hardly a simple result of a single problem, but rather a complex cascade of pathobiological processes and interactions in a complex biochemical environment. The evidence of changes in innate immunity and adaptive immunity during the index event of acute stroke and recovery over next 3-12 months can be easily elicited with simple bedside blood tests such as neutrophil-lymphocyte ratio with well over 300 published papers including several systematic reviews and meta-analyses confirming this. Global standard operating procedures of stroke care dictated by the national and international stroke guidelines at present. It is imperative to explore the evidence of systems biology approach in current stroke guidelines. This is likely to be a key turning point in managing stroke across the continuum. Methods We systematically searched for guideline recommendation on the day-to-day use of peripheral inflammatory markers such as NLR published in the English language between January 1, 2005, and December 2020. Any other evidence of systems biology-based approach or recommendation was explored within the selected guidelines for this scoping review. Only the latest guideline per writing group was selected. Each guideline was analyzed independently by 2 to 4 authors to determine clinical scenarios explained/given, scientific evidence used, and recommendations presented in the context of systems biology. Results The scoping review found 3,830 titles with 119 guidelines from 46 countries included for this review. Stroke-related organizations wrote Sixty-five per cent of the guidelines while national ministries wrote a fewer number of guidelines. We were primarily interested in recommendations for acute management in AIS published in the English language. Fifteen eligible guidelines were identified from 15 different countries/regions. None of the guidelines recommended the routine use of peripheral markers of inflammation, such as NLR, among their acute assessment and management recommendations. None of the existing guidelines explored the systems biology approach to one of the most complex diseases affecting the human brain, stroke. Conclusions This systematic review has identified a significant evidence-practice gap in all existing national stroke guidelines published in English medium as of October 2020. These guidelines included the only current “living stroke guidelines, Stroke Guidelines from Australia with a real opportunity to modernize the living stroke guidelines with systems biology approach and provide 2020 vision towards better stroke care globally. Investigation of complex disease such as stroke is best served through a systems biology approach. One of the easiest places to start is simple blood tests such as total white cell count and NLR. Systems biology approach point us towards simple tools such immune-inflammatory index, Sunshine Prognostic Score which should pave the way for the stroke physician community address the challenges in systems biology approach in stroke care. These challenges include translating bench research to the bedside, managing big data. Working with an interdisciplinary team is also provide a distinct advantage. (shrink)