Protein inhibitor of activated STAT3 (PIAS3) is a member of the protein inhibitor of activated STAT (PIAS) family. PIAS3 is an endogenous suppressor of signal transducer and activator of transcription 3 (STAT3) signaling and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper-activated in various cancers. PIAS3 is the only member of the PIAS family that is indispensable for ATR activation. In response to different types of DNA damage and replication stress, PIAS3 plays multiple roles in ATR activation. STAT3 is implicated in guiding the specification of rod and cone photoreceptors through post-translational modification of key retinal transcription factors.