This paper gives an insight into key factors, which impair enzymatic protein digestion. By nature, some proteins in raw products are already poorly digestible because of structural peculiarities, or due to their occurrence in plant cytoplasmic organelles or in cell membranes. In plant-based protein, molecular and structural changes can be induced by genetic engineering, even if protein is not a target compound class of the genetic modification. Other proteins only become difficult to digest due to changes that occur during the processing of proteinaceous products, such as extruding, boiling, or acidic or alkaline treatment. The utilization of proteinaceous raw materials in industrial fermentations can also have negative impacts on protein digestibility, when reused as fermentation by-products for animal nutrition, such as brewers’ grains. After consumption, protein digestion can be impeded in the intestine by the presence of antinutritional factors, which are ingested together with the food or feedstuff. It is concluded that the encircling matrix, but also molecular, chemical, and structural peculiarities or modifications to amino acids and proteins obstruct protein digestion by common proteolytic enzymes in humans and animals.