Metastasizing cancer cells interact with stroma cells or extracellular matrix (ECM) at target organs. The precise molecular mechanisms underlying the preferential cancer metastasis to bone are not completely elucidated. Mesenchymal stem cells (MSCs) give rise to stromal cells which support homing, proliferation and survival potential of hematopoietic cells, as well as cancer cells homing into the bone marrow. The bone microenvironment is also composed of matrix that is a rich source of immobilized growth factors being released upon remodeling of the bone. Cell adhesion molecules (CAMs) are important players in the cell-cell and cell-matrix interactions in the bone microenvironment. CAMs are divided into several families of molecules expressed by stromal cells and mediate the adhesion of cells to extracellular matrix. Such interactions create specific tissue environment, termed “niche”, affecting gene transcription and differentiation properties of cells. Understanding the bone microenvironment and interactions of cancer cells is important to gain insights into the mechanism that regulates preferential metastasis to the bone.