Metastasis is the primary cause of death in most human cancers, and understanding the molecular mechanisms underpinning this multistep process is fundamental to identifying novel molecular targets and developing more effective therapies. Growth Factor Receptor-bound protein 2 (Grb2) is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. Grb2 signaling is critical for cell cycle progression and actin-based cell motility, and consequently, more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis. These important functions make Grb2 a logical therapeutic target for strategies designed to prevent the spread of solid tumors through local invasion and metastasis. Here we review the role of Grb2 in cancer and specifically in metastasis-related processes, and summarize briefly the development of anti-cancer therapeutics selectively targeting this important adapter protein.