The human adult skeletal system is comprised of 206 bones, along with a network of ligaments, tendons and cartilage. In addition to providing locomotion, the skeletal tissues serve as attachment sites for muscles and as protection for vital soft tissue organs. They harbor hematopoietic tissues (bone marrow) and act as a reservoir for calcium and phosphorus. Just as with any other organ systems, many pathological conditions are associated with musculoskeletal tissues, such as osteoporosis, arthritis, impaired fracture healing, and bone cancers, etc. These diseases affect many people, especially the geriatric population, resulting in pain, stiffness, loss of body function and even mortality. The health-related quality of life in patients with musculoskeletal diseases is signifi cantly reduced, and the rising number of patients suffering from agerelated musculoskeletal diseases can become a signifi cant economic burden in an aging society. To address this issue, many clinical interventions, ranging from new therapeutic treatments to novel surgical procedures, have been developed. Due to the inherent nature of the musculoskeletal system and its clinical relevance, extensive work has been done in the development of nanomaterials scaffolding and the local delivery of functional agents to improve bone repair/regeneration, osseointegration with orthopedic implants and prevention or treatment of postoperative infections. This is a rather crowded fi eld with many high quality reviews being published (Tran and Webster. Wiley Interdiscip Rev Nanomed Nanobiotechnol 1(3): 336–351, 2009; Harvey et al. J Orthop Trauma 24(Suppl 1): S25–S30, 2010; Stylios et al. Injury 38(Suppl 1): S63–S74, 2007; Sato and Webster. Expert Rev Med Devices 1(1): 105–114, 2004; Webster and Ahn. Adv Biochem Eng Biotechnol 103: 275–308, 2007), which the readers are encouraged to explore. This chapter, however, will be mainly focused on several new directions in the fi eld, especially on the use of nanomaterials as carriers to target therapeutic agents to the musculoskeletal lesions after systemic administration. In contrast to the local nanomaterial depot approach, of which the material design and drug release/activation are somewhat arbitrary, the systemically administered carriers would “seek out” its target and deliver the drugs according to the pathological conditions present.