Microfibrillated silk (MFS) is an emerging class of silk-based materials with diverse properties and potential uses. While regenerated silk materials produced using the “bottom-up” approach require complete silk dissolution, the “top-down” microfibrillation of silk fibers only partially disrupts silk’s hierarchical structure to release fibrils that largely retain native silk’s nanocrystalline structure. We have used here the term MFS for exfoliated fibrils with an average diameter of more than 100 nm and the term nanofibrillated silk (NFS) for finer fibrils with a diameter of less than 100 nm. However, these terms microfibrillation, nanofibrillation, MFS, NFS, or fibrillated silk are used interchangeably in the published literature and overall represent exfoliated silk materials. This chapter provides an overview of the processing required to exfoliate silk. Since their use in tissue engineering and biomedicine is in its infancy, this chapter also discusses established bottom-up nanofibrous materials that have been developed for biomedical applications since MFS/NFS are expected to be used in many such applications. Finally, given the significant differences in properties, we provide our perspective on the potential usefulness of MFS in numerous applications including next-generation biomedical products.