As the culprit behind most cancer-related deaths, metastasis is the ultimate challenge in our effort to fight cancer as a life-threatening disease. The explosive growth of metastasis research in the past decade has yielded an unprecedented wealth of information about the tumor-intrinsic and tumor-extrinsic mechanisms that dictate metastatic behaviors, the molecular and cellular basis underlying the distinct courses of metastatic progression in different cancers and what renders metastatic cancer refractory to available therapies. However, integration of such new knowledge into an improved, metastasis-oriented oncological drug development strategy is needed to thwart the development of metastatic disease at every stage of progression.