This chapter addresses the recent progress in synthesizing and applying isolated single-atomic-site (ISAS) materials for sensing/detection against toxic gases (such as NO2, SO2, CO, and O3) and volatile organic compounds (VOCs). ISAS materials are advanced hierarchal nanomaterials with the merits of enhanced atomic dispersion of active catalytic species onto a substrate. A number of metal oxides and hybrid materials have been synthesized and employed for gas and VOC sensing. Their applicability is, however, often confined due to multiple constraints such as limited response to low-polarity molecules, poor selectivity, and sensitivity. In this respect, the use of ISAS materials is advantageous as the synergistic combination of solitary atoms and oxygen vacancy in the substrate can contribute to the enhancement of catalytic efficiency and selectivity. Optimistically, this chapter is expected to help thrash out neoteric fundamental strategies required to expand the applicability of ISAS materials in various sensing/detection applications.