With the growing incorporation of nanomaterials into multiphase industrial processes and consumer products, methods for predicting their behavior in complex systems are in increasing demand. Due to current theoretical limitations, the interactions between nanoparticles and other surfaces cannot always be predicted, necessitating the development of methods that allow for their direct measurement. In this article, we review some recent developments where atomic force microscopy (AFM) probes and opposing surfaces have been modified to enable the direct measurement of nanoparticle interactions. Wet chemistry approaches have been leveraged to assemble nanoparticles on both AFM probes and flat surfaces. AFM tips have been prepared that are terminated with a single 10- to 40-nm gold particle, and carbon nanotube-modified tips have been designed to indent and penetrate the membranes of living cells. Methods for preparing flat surfaces with monolayer coatings of gold or silica nanoparticles of controlled inter-particle spacing have also been developed. In addition, other methods for functionalizing AFM tips with nanoparticulates and their applications are discussed.