Infrared　nonlinear　optical　(IR-NLO)　crystals　as　a　crucial　part　in　all-solid-state　lasers　to　generate　coherent　tunable　laser　beam　in　the　IR　range,　an　important　spectral　interval　for　molecular　spectroscopy,　medical　treatment,　atmospheric　sensing,　and　scientific　researches.　Currently,　commercially　available　IR-NLO　materials　are　very　rare,　limited　to　chalcopyrite　semiconductors　(e.g.,　AgGaS2,　AgGaSe2　and　ZnGeP2).　Unfortunately,　all　of　them　present　certain　limitations,　which　significantly　restrict　their　applications　in　high-power　laser　devices.　For　this　reason,　it　is　extremely　urgent　to　discover　new　type　of　IR-NLO　compounds　with　better　overall　performance.　Yet,　one　of　the　biggest　challenges　is　how　to　create　the　non-centrosymmetric　(NCS)　crystal　structures,　which　is　the　prerequisite　for　the　generation　of　IR-NLO　candidates.　To　accomplish　this　objective,　various　approaches　have　been　introduced　to　design　new　NCS　compounds　and　many　most　advanced　IR-NLO　candidates　have　been　discovered　during　the　past　decades.　Among　them,　molecular　engineering　strategies,　especially　partial　chemical　substitution　based　on　the　known　NCS　or　centrosymmetric　(CS)　maternal　structures,　have　been　confirmed　as　a　simple　yet　highly　effective　method　to　design　and　synthesize　new　high-performance　IR-NLO　materials.　This　strategy　can　not　only　achieve　CS-to-NCS　or　NCS-to-NCS　structural　transformation,　but　also　effectively　improve　the　IR-NLO　performance　of　target　materials　through　simple　element　or　basic　building　unit　substitution.　In　this　review,　33　selected　examples　(including　11　types　of　CS-to-NCS　compounds　and　22　types　of　NCS-to-NCS　compounds)　ranging　from　zero-dimensional　(0D)　isolated　clusters　to　three-dimensional　(3D)　complex　frameworks　designed　through　the　partial　chemical　substitution　strategy　are　discussed　and　summarized　systematically.　Finally,　some　useful　conclusions　and　the　future　development　opportuni-ties　and　challenges　of　IR-NLO　materials　based　on　the　rational　partial　chemical　substitution　are　briefly　discussed.(c)　2023　Elsevier　B.V.　All　rights　reserved.