Metastasis is the leading cause of cancer-related death. Cancer cells must overcome numerous obstacles to colonize distant organs, including evading immune defenses, adapting to supportive niches, and surviving as latent tumor-initiating seeds. These challenges make metastasis an inefficient process, yet current treatments often fail to provide durable responses. Recent advances in experimental models, imaging technologies, and genomic sequencing have provided new insights into the molecular mechanisms of metastatic colonization. Understanding these mechanisms is crucial for developing better prevention and treatment strategies for metastatic cancer. Key aspects of metastatic colonization include the early steps of cancer cell invasion and migration, the role of immune defenses, the formation of supportive niches, and the survival and growth of disseminated tumor cells (DTCs). The inefficiency of metastatic colonization, the existence of latent metastases, and the organ-specific traits of overt metastasis are also discussed. Future research should focus on identifying common mediators of metastatic colonization and developing targeted therapies to prevent and treat metastatic disease.Metastasis is the leading cause of cancer-related death. Cancer cells must overcome numerous obstacles to colonize distant organs, including evading immune defenses, adapting to supportive niches, and surviving as latent tumor-initiating seeds. These challenges make metastasis an inefficient process, yet current treatments often fail to provide durable responses. Recent advances in experimental models, imaging technologies, and genomic sequencing have provided new insights into the molecular mechanisms of metastatic colonization. Understanding these mechanisms is crucial for developing better prevention and treatment strategies for metastatic cancer. Key aspects of metastatic colonization include the early steps of cancer cell invasion and migration, the role of immune defenses, the formation of supportive niches, and the survival and growth of disseminated tumor cells (DTCs). The inefficiency of metastatic colonization, the existence of latent metastases, and the organ-specific traits of overt metastasis are also discussed. Future research should focus on identifying common mediators of metastatic colonization and developing targeted therapies to prevent and treat metastatic disease.