The aim of this chapter is to provide a succinct update about research focused on membrane domains, particularly summarizing new information obtained using imaging techniques. This is presented and discussed in the context of the vast information previously reported using classical biophysical approaches. Thus, a section containing a historical perspective of lipid domains has been added as an introduction, recapitulating how lipid domains came into view and discussing how this phenomenon influenced different models of biological membranes. General but important aspects of the physical basis of lateral heterogeneity in lipid bilayers are discussed, including a synopsis of classical biophysical techniques used to study membrane lateral structure. Later in the chapter the focus shifts to giant vesicles and planar membranes recapitulating information on lipid domains obtained using imaging approaches. This includes a section on experimental results showing correlations between simple lipid mixtures and some specialized natural membranous systems. The chapter ends by discussing the pros and cons of current biological membrane models considering membrane domains, and tackles new challenges and future perspectives on membrane-related studies. This last section includes a critical discussion about the appropriateness of connecting phenomena observed in model membrane systems with their natural counterpart – that is, biological membranes.