Wilson began studying clouds as a meteorologist in 1895. In an effort to duplicate the effects of certain clouds on mountaintops, he devised a way of expanding moist air in a closed container. The expansion cooled the air so that it became supersaturated and moisture condensed on dust particles.

Wilson noted that when he used dust-free air the air remained supersaturated and that clouds did not form until the degree of supersaturation reached a certain critical point. He believed that in the absence of dust the clouds formed by condensing on ions (charged atoms or molecules) in the air. Hearing of the discovery of X rays, he thought that ion formation as a result of such radiation might bring about more intensive cloud formation. He experimented and found that radiation left a trail of condensed water droplets in his cloud chamber. Perfected by 1912, his chamber proved indispensable in the study of nuclear physics and eventually led to the development (by Donald A. Glaser in 1952) of the bubble chamber.

From 1916 Wilson became involved in the study of lightning, and in 1925 he was appointed Jacksonian professor of natural history at the University of Cambridge. Applying his studies of thunderstorms, he devised a method of protecting British wartime barrage balloons from lightning, and in 1956 he published a theory of thunderstorm electricity.