<p>The soil-living social amoeba <i>Dictyostelium</i> species have an interesting life cycle: under nutrient stress, unicellular amoeboid cells assemble into sophisticated multicellular organisms. In addition to its extreme utility as a useful model to investigate cellular differentiation and development, <i>Dictyostelium</i> has also become a source of a diverse repertoire of secondary metabolites with potential biological and pharmacological applications. This review gives a detailed account of the secondary metabolite chemical diversity of <i>Dictyostelium</i>, including polyketides, terpenoids, alkaloids, phenolics, and peptides many of which are presumed to be rare scaffold examples not found in other microbial sources. We describe how genomics developments have highlighted the sheer polyketide synthase (PKS) and terpene synthase (TPS) gene family and sustain this metabolic diversity providing clues into distinct lineage-specific biosynthetic pathways. Isolation, structural elucidation strategies such as chromatographic and spectroscopy methods and their chemical synthesis processes that allow scalable production and studying effect of structure of such bioactive molecules are illustrated. The biological significance of these metabolites is discussed in detail, including their anti-inflammatory, antimicrobial, anticancer, neuroprotective and metabolic regulating properties, and their interactions with critical cellular sign awards. In a prospective, the combination of multi-omics technologies, genome mining, synthetic biology and chemical synthesis will unravel new entities and optimise the yields and therapeutic properties of the products. Taken together, this review highlights the chemically rich metabolite profile and functional diversity of <i>Dictyostelium</i> secondary metabolites and puts forward their possible use as the frontier in natural product-based drug discovery.</p> Graphical abstract <p></p>