Metastatic bone disease is a substantial driver of morbidity and mortality in many cancers. The presence of bone metastases often indicates a worse prognosis for patients. The mechanisms underlying bone metastases and bone loss are complex and involve interaction between the local factors controlling bone remodeling, systemic regulators, cancer cells, the immune system, and pharmaceutical agents. Cancer cells hone to and initiate interactions with bone cells, thereby resulting in an increase or decrease of local bone mass. Osteolytic metastases are clinically important because they place patients at risk of skeletally related events. In the era of precision medicine and targeted therapies, several pathways have been identified that can serve as targets for new drugs. Therefore, it becomes necessary to understand the molecular mechanisms governing normal bone homeostasis and cancer-induced bone loss to optimally use available and emerging therapeutic modalities for the benefit of patients with skeletal metastases. When pharmacologic or radiation therapies do not block the pathogenesis of metastatic cancer-induced bone loss, surgical stabilization and reinforcement procedures are performed based on size of the lesion, location, degree of osteolysis, and pain. These interventions are performed with the goal of improving patient function and overall outcome.