Machine learning has become a central framework for analyzing high-dimensional biological data generated by genomics, transcriptomics, proteomics, single-cell sequencing, and multi-omics technologies. However, predictive modeling is frequently limited by severe class imbalance, where biologically important populations including rare disease subtypes, uncommon molecular states, and low-frequency cell populations are underrepresented. Synthetic oversampling addresses this challenge by increasing minority-class representation, with the Synthetic Minority Oversampling Technique (SMOTE) being the most widely used approach. However, conventional SMOTE assumes that geometric proximity reflects biological similarity, an assumption often violated in high-dimensional, nonlinear, and heterogeneous biological data. This review examines clustering-guided synthetic generation methods that integrate unsupervised learning before oversampling to preserve underlying biological structure. We evaluate partition-based, density-aware, fuzzy, cluster-filtering, and representation-based approaches, emphasizing their mathematical foundations, computational assumptions, and applications in molecular classification, rare population analysis, single-cell modeling, and multi-omics integration. Key challenges including cluster instability, preservation of rare biological populations, synthetic data validation, and distinguishing statistical rarity from biological significance are discussed. Finally, we outline emerging directions involving biological foundation models, graph-based learning, multi-omics representation spaces, and biologically constrained generative frameworks. These advances represent a shift from conventional data balancing toward structure-aware synthetic modeling that preserves meaningful biological organization while improving predictive performance.