Abstract: Chemical flocculants are widely used in treating mature fine tailings (MFT) produced during bitumen extraction processes, among which polymers with high molecular weight (HMW) have demonstrated efficacy in dewatering and clay flocculation. The long polymer chains carry sufficient functional groups to simultaneously interact with multiple clay surfaces, thereby modulating clay surface properties and facilitating the aggregation of clay particles. Significant efforts have been devoted to enhancing the flocculation and dewatering performance of polymer reagents. Despite some successes, the design of new and effective polymer flocculants with desired performance is hindered by the limited fundamental understanding of clay-polymer interaction mechanisms. In this work, interaction mechanisms between polymer flocculants and clay particles are reviewed. Solid flocculation by polymers can be driven by multiple mechanisms, either independently or in combination, due to the diverse properties and solution chemistry involved. Factors that affect the interactions are analyzed, with a particular focus on the effects of clay surface features, pH, ions, and asphaltene. Addressing ongoing debates regarding the synergy of multiple types of polymer segments, the influence of multi-valent ions, and the effects of amphiphilic asphaltene can significantly expedite the design of more effective flocculants and flocculation processes.