Adaptation of muscle or bone to endurance exercise in the horse is of great interest, as specific training and nutrition regimens may maximize performance and prevent injury. Medical manipulation of muscle or bone, while ethically questionable, may also impact the fitness of these tissues. The speed in endurance competitions has increased in recent years, as has the incidence of fractures in endurance horses. The bones of endurance horses experience repetitive loading, resulting in microdamage, which can be repaired or may accumulate into stress fractures that can be catastrophic. This phenomenon is well known in flat-racing horses, but has received less attention in endurance horses. Apparently, front limb fractures are more common than hind limb fractures and most fractures occur in the metacarpal/metatarsal or proximal phalangeal regions in endurance horses, most of which were metatarsal/metacarpal condylar fractures. Information about specific training regimens directed towards prevention of certain bony injuries is available only for flat-racing horses, indicating a need for research in this field to benefit endurance horses. Additionally, bisphosphonate medications that have the potential to significantly affect bony remodeling have been recently approved for use in equines in many countries. While there is no information on specific effects of bisphosphonates on the skeleton in endurance horses, they may be less safe for them, compared with other equine athletes. Genetics determine the predominant muscle fiber types, total fiber number and relative size of fast and slow twitch fibers in horses, favoring certain breeds over others to be successful endurance athletes. Elite endurance horses have a high ratio of type I (slow twitch) and IIA (fast-oxidative glycolytic) muscle fibers and endurance training stimulates transition from fast twitch (type IIX) to slower twitch fibers (type IIA and I). Endurance training also causes hypertrophy of type I and IIA fiber types, resulting in increased aerobic and decreased anaerobic capacity of the muscle. On a cellular level, these changes are induced by quantitative and qualitative alterations in gene expression of both regulatory and structural genes.