Bone infections are devastating complications in orthopedics due to biofilm formation. Treatment requires high antibiotic doses, which may lead to systemic toxicity thus limiting the drug therapeutic effectiveness. In this context, nanoparticles are well-known controlled release drug carriers that are able to modulate release rate, versatile in terms of administration routes and may be used as local delivery systems. Regarding bone infections, although nanoparticles are a promising strategy for overcoming biofilm tolerance, there are clearly technical, safety, regulatory and clinical challenges that need to be overcome before such nanomedicines may be translated into clinical use. In this paper, we present a critical overview on the high expectations against the real potential of the nanotechnological approaches to bone infection treatment.