Hyperactive ERK signaling has a well-defined role in cancer biology. Targeting this signaling node for cancer therapy has achieved promising outcomes in clinic. However, significant challenges persist to effectively tackle ERK signaling in cancers with long-term effects. Overcoming these challenges needs deeper understanding of underlying molecular mechanisms that are involved in the regulation of ERK signaling in both cancer and normal cells with or without therapeutic interventions. In this book chapter, we summarized the most recent findings of the regulatory mechanism of ERK signaling and the therapeutic approaches targeting hyperactive ERK signaling in cancers and prospected the potential strategies for developing durable treatments. We hope these interactive discussions among mechanistic studies, therapeutic development, and clinical treatment would have important implications in cancer biology.