The ubiquitin-proteasome system (UPS) and UBL pathways, such as SUMOylation and NEDDylation are critical in protein homeostasis and activities in vivo and are emerging as the target of new strategies to treat many acute and chronic human diseases, such as infections, inflammation and cancers. Cytokines, including interferons (IFNs) and Toll-like receptors, are the first line of defense for host and have crucial roles in inducing immune responses to the invading pathogens. SUMOylation inhibits the signaling pathways of IFNs and Toll-like receptors, the JAK-STAT and the NFκB pathways, respectively. NEDDylation is required for activating the Cullin family proteins, which mediate protein degradation as part of apoptosis in many solid tumors. Although only one proteasome inhibitor with a novel mechanism has been approved for marketing so far, targeting SUMOylation and other UBLs could lead to a new paradigm for therapeutic agents for a variety of pathological conditions. Recently, the first NEDDylation inhibitor, MLN4924, was shown to have great potential as a novel anti-tumor drug and is in clinical development. A family of other UBLs is emerging as different protein modifiers for different biological processes and may serve as potential drug targets in the future.