An incomplete view of the mechanisms that drive metastasis, the primary cause of melanoma-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions and cellular plasticity drives the metastatic cascade. We performed a longitudinal and exhaustive analysis of the diversity and trajectories of melanoma cell states during metastatic dissemination by combining single-cell profiling techniques with lineage tracing in clinically-relevant mouse models of melanoma. We identified one specific melanoma cell state, which is present in both mouse and human primary tumors, that drives the metastatic process, but not primary tumor growth. We deciphered the gene regulatory network underlying this particular state and developed therapeutic modalities that prevent phenotype switching into this state. This study highlights how understanding the magnitude and dynamics of non-genetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on non-genetic tumor evolution.