Lichen natural products are a tremendous source of new bioactive chemical entities for drug discovery. The ability to survive in harsh conditions can be directly correlated with the production of some unique lichen metabolites. Despite the potential applications, these unique metabolites have been underutilized by pharmaceutical and agrochemical industries due to their slow growth, low biomass availability, and technical challenges involved in their artificial cultivation. At the same time, DNA sequence data have revealed that the number of encoded biosynthetic gene clusters in a lichen is much higher than in natural products, and the majority of them are silent or poorly expressed. To meet these challenges, the one strain many compounds (OSMAC) strategy, as a comprehensive and powerful tool, has been developed to stimulate the activation of silent or cryptic biosynthetic gene clusters and exploit interesting lichen compounds for industrial applications. Furthermore, the development of molecular network techniques, modern bioinformatics, and genetic tools is opening up a new opportunity for the mining, modification, and production of lichen metabolites, rather than merely using traditional separation and purification techniques to obtain small amounts of chemical compounds. Heterologous expressed lichen-derived biosynthetic gene clusters in a cultivatable host offer a promising means for a sustainable supply of specialized metabolites. In this review, we summarized the known lichen bioactive metabolites and highlighted the application of OSMAC, molecular network, and genome mining-based strategies in lichen-forming fungi for the discovery of new cryptic lichen compounds. lichen, natural products, bioactivity, pks, osmac strategy, genome mining, biosynthetic gene clusters, polyketide synthase gene, secondary metabolites, usnic acid, norstictic acid, heterologous expression, protolichesterinic acid, antimicrobial activity, cultured mycobionts, protocetraric acid