Simple SummaryThis review describes how osteocytes, the most abundant cells in bone, act in cancers that grow in bone. It summarizes how cancer cells reprogram osteocytes to participate in processes associated with tumor growth, cancer cell survival, migration, angiogenesis, and bone destruction. These changes ultimately facilitate the spread of cancer in the bones and promote bone disease. It also discusses some of the identified signaling pathways mediating these processes and the therapeutic strategies to target them.AbstractThe tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanisms responsible for the dependency between cancer cells and bone cells. In this review, we focus on osteocytes, long-lived cells residing in the mineral matrix that have recently been identified as key players in the spread of cancer in bone. We highlight the most recent discoveries on how osteocytes support tumor growth and promote bone disease. Additionally, we discuss how the reciprocal crosstalk between osteocytes and cancer cells provides the opportunity to develop new therapeutic strategies to treat cancer in the bone.