Research on nanoparticles has evolved into a major topic in chemistry. Concerning biomedical research, nanoparticles have decisively entered the field, creating the area of nanomedicine where nanoparticles are used for drug delivery, imaging, and tumor targeting. Besides these functions, scientists have addressed the specific ways in which nanoparticles interact with biomolecules, with proteins being the most prominent example. Depending on their size, shape, charge, and surface functionality, specifically designed nanoparticles can interact with proteins in a defined way. Proteins have typical dimensions of 5-20 nm. Ultrasmall nanoparticles (size about 1-2 nm) can address specific epitopes on the surface of a protein, for example, an active center of an enzyme. Medium-sized nanoparticles (size about 5 nm) can interact with proteins on a 1:1 basis. Large nanoparticles (above 20 nm) are big in comparison to many proteins and therefore are at the borderline to a two-dimensional surface onto which a protein will adsorb. This can still lead to irreversible structural changes in a protein and a subsequent loss of function. However, as most cells readily take up nanoparticles of almost any size, it is easily possible to use nanoparticles as transporters for proteins into a cell, for example, to address an internal receptor. Much work has been dedicated to this approach, but it is constrained by two processes that can only be observed in living cells or organisms. First, nanoparticles are usually taken up by endocytosis and are delivered into an intracellular endosome. After fusion with a lysosome, a degradation or denaturation of the protein cargo by the acidic environment or by proteases may occur before it can enter the cytoplasm. Second, nanoparticles are rapidly coated with proteins upon contact with biological media like blood. This so-called protein corona influences the contact with other proteins, cells, or tissue and may prevent the desired interaction. Essentially, these effects cannot be understood in purely chemical approaches but require biological environments and systems because the underlying processes are simply too complicated to be modeled in nonbiological systems. The area of nanoparticle-protein interactions strongly relies on different approaches: Synthetic chemistry is involved to prepare, stabilize, and functionalize nanoparticles. High-end analytical chemistry is required to understand the nature of a nanoparticle surface and the steps of its interaction with proteins. Concepts from supramolecular chemistry help to understand the complex noncovalent interactions between the surfaces of proteins and nanoparticles. Protein chemistry and biophysical chemistry are required to understand the behavior of a protein in contact with a nanoparticle. Finally, all chemical concepts must live up to the "biological reality", first in cell culture experiments in vitro and finally in animal or human experiments in vivo, to open new therapies in the 21st century. This interdisciplinary approach makes the field highly exciting but also highly demanding for chemists who, however, have to learn to understand the language of other areas.