Mexico is the center of origin and diversification of domesticated chile (Capsicum annuum L.). Chile is conceived and employed as both food and medicine in Mexico. In this context, the objective of this paper is to describe and analyze the cultural role of chile as food and as medicine for the body and soul in different cultures of Mexico. To write it, we relied on our own fieldwork and literature review. Our findings include a) the first matrix of uses of chile across 67 indigenous and Afrodescendants cultures within Mexican territory and b) the proposal of a new model of diversified uses of chile. Traditional knowledge, uses and management of chile as food and medicine form a continuum (i.e., are not separated into distinct categories). The intermingled uses of Capsicum are diversified, deeply rooted and far-reaching into the past. Most of the knowledge, uses and practices are shared throughout Mexico. On the other hand, there is knowledge and practices that only occur in local or regional cultural contexts. In order to fulfill food, medicinal or spiritual functions, native communities use wild/cultivated chile.