Up-frameshift protein 1 (UPF1) is an evolutionarily conserved protein with RNA/DNA-dependent ATPase and RNA helicase activity. The protein is well known for its central role in nonsense-mediated mRNA decay (NMD), which eliminates aberrant mRNAs harboring premature termination codon (PTC), preventing the accumulation of nonfunctional or potentially harmful truncated proteins. NMD is also involved in the regulation of the state-levels of many normal physiological mRNAs. Moreover UPF1 is not only a key player in NMD but is also involved in non-NMD RNA degradation, such as staufen1 (STAU1)-mediated mRNA decay (SMD) and replication-dependent histone mRNA decay. Thus, UPF1 is an important factor for the RNA quality control system and the regulation of physiological gene expression. Further, recent studies have clarified that UPF1 contributes to DNA replication, DNA repair, telomere metabolism, and stabilization of HIV-1 genomic RNA. In the review, we summarize numerous functions of UPF1.