Starch is the most abundant glycemic carbohydrate in the human diet. Consumption of starch-rich food products that elicit high glycemic responses has been linked to the occurrence of noncommunicable diseases such as cardiovascular disease and diabetes mellitus type II. Understanding the structural features that govern starch digestibility is a prerequisite for developing strategies to mitigate any negative health implications it may have. Here, we review the aspects of the fine molecular structure that in native, gelatinized, and gelled/retrograded starch directly impact its digestibility and thus human health. We next provide an informed guidance for lowering its digestibility by using specific enzymes tailoring its molecular and three-dimensional supramolecular structure. We finally discuss in vivo studies of the glycemic responses to enzymatically modified starches and relevant food applications. Overall, structure-digestibility relationships provide opportunities for targeted modification of starch during food production and improving the nutritional profile of starchy foods.