Although cytoplasmic dynein probably appeared first during evolution, its discovery did not occur until research into axonemal dynein was well advanced. This chapter traces the initial discovery of cytoplasmic dynein as one of the high molecular weight microtubule associated proteins in brain, followed gradually by the identification of a versatile collection of dynein associated proteins. Various protein complexes significantly modulate the properties of cytoplasmic dynein and its interaction with different cargoes. The focus in this chapter is on the way that these properties have been investigated in vitro.