Ganoderma species are among the most destructive fungal pathogens affecting plantation and forest crops, causing Basal stem rot (BSR) and root rot that lead to severe economic losses. Understanding the molecular mechanisms underlying the Ganoderma pathosystem is critical for early detection and effective disease management. This chapter explores the enzymatic systems involved in lignin and cell wall degradation, the roles of secondary metabolites and toxins in pathogenesis, and effector proteins that disrupt host immune signalling. It further examines Ganoderma’s strategies to evade plant defenses, including oxidative stress tolerance and gene regulatory mechanisms. Cutting-edge functional validation tools—such as CRISPR-Cas9, RNA interference (RNAi), and host-induced gene silencing (HIGS)—are discussed as promising approaches for elucidating pathogenicity-related genes. The chapter also highlights advances in molecular diagnostics, virulence biomarkers, and resistance breeding strategies, contributing toward integrated and sustainable management of Ganoderma-induced diseases.