The brain is a privileged site of systemic cancer metastasis. The stages of the metastatic journey from the periphery to the brain are driven by molecular events that tie the original site of disease to the distant host tissue. This preference is not arbitrary but rather a directed phenomenon that includes such critical steps as angiogenesis and the preparation of the premetastatic niche. It appears that the connection between naive brain and cancer cells is made in advance of any metastatic breach of the blood-brain barrier. This contributes to the preferential homing of cancer cells to the brain. Delineation of the guidance mechanisms and elements that influence cancer cell motility and dormancy are important for the advancement of treatment modalities aimed at the remediation of this devastating disease.