IFN-lambdas, including IFN-lambda1, IFN-lambda2, and IFN-lambda3, also known as IL-29, IL-28A, or IL-28B, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. The IFN-lambdaR complex consists of a unique ligand-binding chain, IFN-lambdaR1 (also designated IL-28Ralpha), and an accessory chain, IL-10R2, which is shared with receptors for IL-10-related cytokines. IFN-lambdas signal through the IFN-lambdaR and activate pathways of JAK-STATs and MAPKs to induce antiviral, antiproliferative, antitumor, and immune responses. In this review, we summarize recent findings about the biology of IFN-lambdas and their pathophysiological roles in viral infection, cancer, and immune responses of the innate and adaptive arms.