Vine and wine are an abundant source of stilbenoids that constitute a large class of compounds, including a series of monomers and oligomers (dimers, trimers, tetramers). Stilbenoids can reach a level of over 100 mg L−1 in red wine. Several epidemiological studies have correlated the consumption of grapes and wines with significant health benefits. The most studied stilbenoid, resveratrol, exhibits multiple biological activities across multiple diseases including cancer and cardiovascular and neurodegenerative diseases. This compound shows promise in both the prevention and the treatment of these diseases. Moreover, resveratrol mimics calorie restriction and extends the lifespan in species ranging from yeast to multicellular animals (not in normal mammals) by a sirtuin-dependent mechanism. Resveratrol is well absorbed yet rapidly metabolized; however, the tissue concentrations found in some studies in animals and humans are compatible with its biological activities. Resveratrol is well tolerated at doses of up to 1 g day−1 in human and does not cause serious adverse events up to 5 g day−1. Interestingly, other wine and grape stilbenoids such as piceatannol, pterostilbene, viniferins, and vitisins also have beneficial activities. In this chapter, we have discussed chemistry and protective role of stilbenoids in general, and resveratrol in particular, during various pathological conditions such as neurodegeneration, neuroinflammation, cancer, cardiovascular diseases, and antiaging process. Works related to bioavailability and clinical trials of resveratrol are also presented.