Enzyme inactivation generated by the spray drying process and attempts to describe both the possible causes and the mechanisms thereof constitute a subject matter of many scientific papers. In the present paper, the analysis of the most important causes of inactivation is presented, and some examples are given to illustrate the mechanisms described. The causes of inactivation include: impact of increased temperature, adverse effect of removing water from the system, adverse effect of protein adsorption on interfacial surface, and mechanical damages. Some methods and mechanism applied to stabilize the enzyme activity during spray-drying are described and exemplified, such as: water replacement, glassy state, and interfacial adsorption.