The musculoskeletal system is composed of bone, muscles, tendons, and ligaments. As an essential component of the human anatomy, it serves as the mechanical support for the body and protects vital organs and bone marrow. It also serves as a reserve of ions, especially calcium and phosphate, for the maintenance of serum homeostasis. The coordination of the skeleton with attached muscles, ligaments, and tendons provides locomotion for the human body. Dysfunction of any component of the musculoskeletal system can cause various forms of diseases. As an example, imbalanced bone remodeling favoring bone resorption leads to osteoporosis, a disease characterized by low bone mass and micro-architectural deterioration of bone tissue resulting in an increased fracture risk. Rheumatoid arthritis, on the other hand, is an autoimmune disorder that damages both articular bone and cartilage, causing significant pain and loss of movement. Furthermore, several types of cancer have bone as their primary sites of metastasis. Osteomyelitis due to bone infection of Staphylococcus aureus is hard to treat and sometimes has to be resolved with surgical debridement or even amputation. The understanding of the pathophysiology of musculoskeletal diseases has been greatly improved during the past few decades. Numerous therapeutic targets have been identified with many new drugs in clinical applications. One of the most notable drug classes that have been developed is the bisphosphonates (BPs). They are stable analogues of naturally-occurring pyrophosphate and have been used extensively in the treatment of osteoporosis, Paget’s disease, cancer bone metastasis, and in children with osteogenesis imperfecta. The main biological effect of BPs is inhibition of osteoclast activities, but they also interact with other cells such as osteocytes. The most interesting property of BPs, however, is their strong bone affinity, which affords them unique pharmacokinetic/biodistribution profiles favoring fast deposition and long residence in the skeleton. This osteotropicity is the key to the BPs’ success, or this class of poorly oral available drugs (< 1 %) may have never entered clinical applications. BPs are an unique group of molecules with both osteotropicity and biological activities encoded in the same chemical structures. For other musculoskeletal disease drugs, however, delivery strategies must be employed to incorporate tissue specificity. The field of targeted delivery for musculoskeletal diseases is still in its early development with many significant challenges. The targeting moieties used so far are limited to BPs and aspartic acid peptides. Though considered as the most potent bone-targeting moiety, the usage of BPs in targeted delivery systems may be hampered by the recently raised concern of BP-associated osteonecrosis of the jaw. Several types of delivery vehicles have been developed for musculoskeletal diseases. For a particular disease condition, the delivery vehicle must be chosen wisely, taking into consideration the nature of the disease, the potency of the drug, and the pharmacokinetics of the delivery vehicle. It is easy to bring delivery systems to well-vascularized skeletal regions, but transportation to areas with limited blood supply (where the medication is probably most needed) can be challenging. Stability of the drug during formulation and delivery is another factor to be considered. This is especially important when the delivery cargo is a biological. Several leading groups have been invited to contribute to this theme section. Dr. Miyamoto’s group investigated the aspartic acid peptide-based delivery of anti-microbial quinolones for improved treatment of osteomyelitis. Previously, they have successfully delivered alkaline phosphatase and estradiol to the bone using a similar strategy. The Utah group led by Drs. Miller and Kopecek reported the polymer-based osteotropic delivery of prostaglandin E1 (a potent bone anabolic agent) for the treatment of osteoporosis. Its promising results offers the first evidence of the efficacy of bone-targeted anabolic therapy. Dr. Uludag’s group is best known for their bone-targeted delivery of biologicals using bisphosphonate conjugation. In this theme section, they focused on another important issue and investigated the bioactivity of bone growth factors entrapped in nanoparticles for local or systemic bone regeneration. Finally, my group described the design, synthesis, and in vivo evaluation of a well-defined polymer-dexamethasone conjugate for the highly effective treatment of rheumatoid arthritis. Different from other bone-targeting delivery systems, the specific delivery to arthritic joints is mainly due to the enhanced vascular permeability to macromolecules found in the inflammed synovium tissue. It has been a fun and exciting experience to work with my colleagues on this theme section. I deeply appreciate their contributions and certainly hope that the work presented here may be intellecturally stimulating and attract the interests of other scientists to join us to persue this very promising research direction. Enjoy!