Polyphenols, such as flavonoids found in a variety of plant species, have attracted the attention of scientists, the public, and the media due to their potential use as nutraceutical products. The high quantities of polyphenols found in some berry species, e.g. Vaccinium species such as blueberries and lingonberries, and their reported antioxidant and anti-inflammatory proper- ties, could be beneficial for brain aging and neurodegenerative disorders. The neuroprotective potential of various polyphenolic compounds have been validated using a variety of in vivo and in vitro techniques, and they are often evaluated initially using in vitro cell culture techniques in order to establish toxicity and effective concentrations. Both in vivo and in vitro methodologies have their respective advantages and disadvantages, including, but not limited to, cost, time, use of resources and technical limitations. This presentation is meant to elaborate on the inherent benefits and drawbacks of in vitro and in vivo methods for assessing neuroprotection, especially in light of proper evaluation of compound efficacy and neural bioavailability. For example, in vivo studies can better evaluate the effects of protective compounds and/ or their metabolites on various tissues, including the brain, in the whole animal, whereas in vitro studies can better discern the cellular and/or mechanistic effects of compounds. In particular, I aim to address the question of appropriate and accurate extrapolation of findings from in vitro experi- ments where compounds are often directly applied to cellular extracts, potentially at higher concentrations than would ever cross the blood-brain barrier to the more complex scenario of neuroprotection due to pharmaco- dynamics in vivo.