During the past two decades, the incidence of invasive fungal infections has been increasing dramatically. Clinical available antifungal agents have several drawbacks such as limited potency and spectrum, drug related toxicity, non-optimal pharmacokinetics, and severe resistance. There is an emergent need to develop new antifungal drugs with novel chemical structures and novel mechanism of action. This review will focus on the most significant achievements in the discovery of antifungal lead structures within last few years. In particular, we pay more attention on the structureactivity relationship of antifungal leads and provide perspectives for future antifungal drug discovery.