Small co-solute molecules containing unpaired electrons can impart strong perturbations on nuclear shielding and nuclear relaxation of dissolved compounds, and thereby form a potent class of non-covalent probes for molecular science. These paramagnetic co-solutes range from exquisite lanthanoid and transition metal complexes to a molecule as simple as dioxygen. In this chapter, we discuss the various effects that can be observed due to paramagnetic co-solutes, and we highlight how these effects have spurred the buildout of their application to protein science. For example, dioxygen is a very sensitive probe able to identify internal cavities in proteins, whereas neutral gadolinium chelates have become key in the structure determination of protein complexes in solution.