The benefit of using positive allosteric modulators of protein function in the therapy of human diseases is becoming more apparent. The advantage of positive allosteric modulators is that they can possess specificity and selectivity profiles as well as concentration-independent limits on activity that can significantly reduce off-target effects in vivo. However, many current screening paradigms are not designed to discover positive allosteric modulators, and modulators that are discovered serendipitously can be overlooked during the hit-picking process. The conditions needed to discover positive allosteric modulators in a HTS are reasonable and simple to implement, generally requiring consideration of the ligand concentration in a screen. Other considerations in the screening for positive allosteric modulators can be derived from the analysis of simple kinetic schemes that describe the interactions of ligands and modulators with different protein targets.