Clathrin-independent endocytosis (CIE) is the process of cellular uptake of various particles, including pathogens, without the coat protein clathrin. It occurs commonly in mammalian cells and is regulated by protein-lipid composition of the cell membranes. Understanding of different routes of CIE allowed the identification of novel molecular mechanisms involved in uptake of molecules and cell signaling and explained their role in pathological processes. In this paper we characterize diseases associated with genetic defects of proteins involved in CIE and the relationship between expression of these proteins and pathology of atherosclerosis, hypercholesterolemia, diabetes and neoplasia. The role of CIE in bacterial, viral, fungal, and protozoal infections is also presented. In the second part we describe the plausible use of clathrin-independent endocytosis in increasing drug absorption, their penetration through biological membranes, and the design of specific nanocarriers for selective cell uptake.