Membrane proteins can be classified into two main categories—integral and peripheral membrane proteins—depending on the nature of their membrane interaction. Peripheral membrane proteins are highly unique amphipathic proteins that interact with the membrane indirectly, using electrostatic or hydrophobic interactions, or directly, using hydrophobic tails or GPI-anchors. The nature of this interaction not only influences the location of the protein in the cell, but also the function. In addition to their unique relationship with the cell membrane, peripheral membrane proteins often play a key role in the development of human diseases such as African sleeping sickness, cancer, and atherosclerosis. This review will discuss the membrane interaction and role of periplasmic nitrate reductase, CymA, cytochrome c, alkaline phosphatase, ecto-5’-nucleotidase, acetylcholinesterase, alternative oxidase, type-II NADH dehydrogenase, and dihydroorotate dehydrogenase in certain diseases. The study of these proteins will give new insights into their function and structure, and may ultimately lead to ground-breaking advances in the treatment of severe diseases.