Caffeine is present in coffee and many other beverages and is the most widely used central nervous system stimulant. Coffee drinking or caffeine supplementation may have a role in preventing cardiometabolic and endocrine disease, neuroinflammation, cancer, and even all-cause mortality. Other aspects are either less known or controversial, including the effects on the brain-gut axis, neurodevelopment, behavior, pain, muscle-skeletal health, skin or sexual function. Studies focusing on special populations (neonates, children, adolescents, athletes, elderly, pregnant and nonpregnant women), or interactions with other drugs and foods, are relatively scarce but of obvious interest. Other compounds present in coffee and other caffeinated food stuffs may affect caffeine´s physiological effects with a tremendous impact on health. This Special Issue, which contains twenty-one manuscripts, has focused on some of these varied topics, providing further evidence of the multiple health benefits that coffee/caffeine intake may exert in humans, at least in specific populations (with a particular genetic profile or suffering from specific diseases). However, the specific effects in the different organs and systems, as well as the mechanisms involved are not yet clear. Furthermore, within the current context aiming to sustainable development, the coffee plant Coffee sp. and its so-far relatively neglected by-products are expected to become soon a source of ingredients for new functional foods whose properties will need to be precisely determined. We hope the readers of this Special Issue will find inspiration for new studies on the topic.