The success of the protein structure-function paradigm was thought to suggest that a protein could only function with a well-defined three-dimensional structure. This view is based on more than 60 000 high-resolution structures in the Protein Data Bank, which in many cases enable the interpretation of function in terms of structure. There are many observations, however, that argue for a novel family of proteins, which apparently exist and function without a well-defined structure. Studies of these intrinsically disordered proteins (IDPs) are in the spotlight of current structural biology, leading to a rapid extension and transformation of the structure-function paradigm. Predictions based on the biased sequence features of IDPs suggest that structural disorder reaches very high proportions in higher eukaryotes. Protein disorder is particularly prevalent in proteins with regulatory and signaling functions. Detailed analyses have shown that structural disorder is not a uniform structural state, but a continuum from a fully disordered (random-coil) state to compact states. Among a range of physical techniques, NMR provides the most detail and insight into the structural ensemble of IDPs, and it also has the potential of reporting on the in vivo state and interactions of these proteins. In this chapter, we provide an overview of concepts and recent developments in this rapidly advancing area of structural biology.