An in vitro cell-based screening method for identifying test compounds having improved cellular specificity as compared to a first compound that is an inhibitor or activator of a protein that is capable of eliciting a detectable phenotypic characteristic, which comprises: a) providing a test cell which expresses the protein and is capable of eliciting a detectable phenotypic characteristic linked to the presence and functional activity of the protein in the cell and wherein said phenotypic characteristic is also capable of being modulated by an inhibitor or activator (phenoresponse); b) providing a control cell which expresses the protein at a lower level or does not express the protein and is capable of eliciting the phenoresponse; c) measuring the modulation of the phenoresponse of the test cell treated with the first compound, d) measuring the modulation of the phenoresponse of the control cell treated with the first compound, e) measuring the modulation of the phenoresponse identified and selected in steps a-d of the test cell treated with test compounds; f) measuring the modulation of the phenoresponse identified and selected in steps a-d of the control cell treated with the test compounds; g) determining the cellular specificity gap of the test compounds by measuring the ability of the test compounds to modulate the selected phenoresponse in the test cell relative to the ability of said compounds to modulate the same phenoresponse in the control cell, wherein the CSG is quantified by dividing the IC 50 of the compounds on the phenoresponse of the control cell by the IC 50 of the compounds on the phenoresponse of the test cell; and h) identifying a test compound as having improved cellular specificity if the CSG of the test compound is greater than the CSG of the first compound. a) providing a test cell which expresses the protein and is capable of eliciting a detectable phenotypic characteristic linked to the presence and functional activity of the protein in the cell and wherein said phenotypic characteristic is also capable of being modulated by an inhibitor or activator (phenoresponse); b) providing a control cell which expresses the protein at a lower level or does not express the protein and is capable of eliciting the phenoresponse; c) measuring the modulation of the phenoresponse of the test cell treated with the first compound, d) measuring the modulation of the phenoresponse of the control cell treated with the first compound, e) measuring the modulation of the phenoresponse identified and selected in steps a-d of the test cell treated with test compounds; f) measuring the modulation of the phenoresponse identified and selected in steps a-d of the control cell treated with the test compounds; g) determining the cellular specificity gap of the test compounds by measuring the ability of the test compounds to modulate the selected phenoresponse in the test cell relative to the ability of said compounds to modulate the same phenoresponse in the control cell, wherein the CSG is quantified by dividing the IC 50 of the compounds on the phenoresponse of the control cell by the IC 50 of the compounds on the phenoresponse of the test cell; and h) identifying a test compound as having improved cellular specificity if the CSG of the test compound is greater than the CSG of the first compound.