Fusarium oxysporum, a ubiquitous soilborne pathogen, causes devastating vascular wilt in more than 100 plant species and ranks 5th among the top 10 fungal plant pathogens. It has emerged as a human pathogen, too, causing infections in immune-compromised patients. Therefore, it is important to gain insight into the molecular processes involved in the pathogenesis of this transkingdom pathogen. A complex network comprising interconnected and overlapping signal pathways-mitogen-activated protein kinase signaling pathways, Ras proteins, G-protein signaling components and their downstream pathways, components of the velvet (LaeA/VeA/VelB) complex, and cAMP pathways-is involved in perceiving the host. This network regulates the expression of various pathogenicity genes. However, plants have evolved an elaborate protection system to combat this attack. They, too, possess intricate mechanisms at the molecular level which, once triggered by pathogen attack, transduce signals to activate defense response. This review focuses on understanding and presenting a wholistic picture of the molecular mechanisms of F. oxysporum-host interactions in plant immunity.