IFN-γ, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer cells, is able to bind to the IFN-γ receptor (IFNγR) and in turn activate the Janus kinase (JAK)-signal transducer and transcription protein (STAT) pathway and induce expression of IFN-γ-stimulated genes. IFN-γ is critical for innate and adaptive immunity and aberrant IFN-γ expression and functions have been associated with different human diseases. However, the IFN-γ/IFNγR signaling could be a double-edged sword in cancer development because the tissue microenvironments could determine its anti- or pro-tumorigenic activities. The IFNγR protein consists of two IFNγR1 and IFNγR2 chains, subunits of which play different roles under certain conditions. This review assessed IFNγR polymorphisms, expression and functions in development and progression of various human diseases in an IFN-γ-dependent or independent manner. This review also discussed tumor microenvironment, microbial infection, and vital molecules in the IFN-γ upstream signaling that might regulate IFNγR expression, drug resistance, and druggable strategy, to provide evidence for further application of IFNγR. Display omitted •IFN-γ/IFNγR signaling is a double-edged sword in the development of human diseases.•IFNγR1 and IFNγR2 play different roles in an IFN-γ-dependent or independent manner.•IFN-γR polymorphism, expression and functions are associated with different diseases.•IFN-γ upstream signaling regulates IFNγR, tumor development and druggable strategy.•We explore IFNγR1/2-related actions to provide evidence for further IFNγR application.