The ABC (ATP-binding cassette) protein superfamily is a ubiquitous and functionally versatile family of proteins that is conserved from archaea to humans. In eukaryotes, most of these proteins are implicated in the transport of a variety of molecules across cellular membranes, whereas the remaining ones are involved in biological processes unrelated to transport. The biological functions of several ABC proteins have been described in clinically important parasites and nematode worms and include vesicular trafficking, phospholipid movement, translation and drug resistance. This chapter reviews our current understanding of the role of ABC proteins in drug resistance and treatment failure in apicomplexan, trypanosomatid and amitochondriate parasites of medical relevance as well as in helminths.