The paper demonstrates how the Hard-Soft Acid Base (HSAB) theory can be used as a valuable criterion in the selection process of semiconducting metal oxides (MOX) suitable as sensing layers for ammonia detection. Six different cases of ammonia detection performed by chemiresistive sensors employing MOX and related nanocomposites as sensing layers are identified and discussed. The role of HSAB as an efficient selection tool for appropriate sensing layer (any type of gas), is further reinforced by analyzing and discussing literature results on MOX-based trimethylamine sensing layers. By analyzing the operation of a fiber-optic ammonia sensor, we demonstrate that the HSAB principle can be also successfully applied to the selection of sensing layers for detectors employing other sensing principles, different than the chemiresistive one. Changing the sensing paradigm (i.e., the amino groups-based compounds are part of the sensing layer, rather than part of the analyte), the paper shows that these types of molecules (polymers, carbon nanotubes, ionic liquids) are appropriate constituents of a CO 2 sensing layer, in full accordance to the HSAB criteria.