The development of antibiotics revolutionized human health, providing a simple cure for once dreaded diseases such as tuberculosis. However, widespread production, use, and mis-use of antibiotics have contributed to the next-generation concern for global public health: the emergence of multiple drug-resistant (MDR) infectious organisms (a.k.a. “superbugs”). Recently, nanotechnology, specifically the use of nanomaterials (NMs) with antimicrobial activity, has been presented as a new defense against MDR infectious organisms. We discuss the potential for NMs to either circumvent microbial resistance or induce its development in light of our current state of knowledge, finding that this question points to a need for fundamental research targeting the molecular mechanisms causing antimicrobial activity in NMs. In the context of current microbial nanotoxicology studies, particularly reductionist laboratory studies, we offer suggestions and considerations for future research, using an illustrative example from our work with silver nanoparticles.