Domains are considered to be the building blocks of protein structures. A protein can contain a single domain or multiple domains, each one typically associated with a specific function. The combination of domains determines the function of the protein, its subcellular localization and the interactions it is involved in. Determining the domain structure of a protein is important for multiple reasons, including protein function analysis and structure prediction. This chapter reviews the different approaches for domain prediction and discusses lessons learned from the application of these methods.