Molina joined the lab of Professor F. Sherwood Rowland in 1973 as a postdoctoral fellow. Here, Molina continued Rowland's pioneering research into "hot atom" chemistry, which is the study of chemical properties of atoms with excess translational energy owing to radioactive processes.
This study soon led to research into chlorofluorocarbons (CFCs), apparently harmless gases that were used in refrigerants, aerosol sprays, and the making of plastic foams. CFCs were being released by human activity and were known to be accumulating in the atmosphere. The basic scientific question Molina asked was "What is the consequence of society releasing something to the environment that wasn't there before?"
Rowland and Molina had investigated compounds similar to CFCs before. Together they developed the CFC ozone depletion theory, by combining basic scientific knowledge about the chemistry of ozone, CFCs and atmospheric conditions with computer modelling. First Molina tried to figure out how CFCs could be decomposed. At lower levels of the atmosphere, they were inert. Molina realized that if CFCs released into the atmosphere do not decay by other processes, they will continually rise to higher altitudes. Higher in the atmosphere, different conditions apply. The highest levels of the stratosphere are exposed to the sun's ultraviolet light. A thin layer of ozone floating high in the stratosphere protects lower levels of the atmosphere from that type of radiation.
Molina theorized that photons from ultraviolet light, known to break down oxygen molecules, could also break down CFCs, releasing a number of products including chlorine atoms into the stratosphere. Chlorine atoms (Cl) are radicals: they have an unpaired electron and are very reactive. Chlorine atoms react easily with ozone molecules (O), removing one oxygen atom to leave O and chlorine monoxide (ClO).
:Cl· +  → ClO· + 
ClO is also a radical, which reacts with another ozone molecule to release two more O molecules and a Cl atom.
:ClO· +  → Cl· + 2
The radical Cl atom is not consumed by this pair of reactions, so it remains in the system.
Molina and Rowland predicted that chlorine atoms, produced by this decomposition of CFCs, would act as an ongoing catalyst for the destruction of ozone. When they calculated the amounts involved, they realized that CFCs could start a seriously damaging chain reaction to the ozone layer in the stratosphere.
In 1974, as a postdoctoral researcher at University of California, Irvine, Molina and F. Sherwood Rowland co-authored a paper in the journal Nature highlighting the threat of CFCs to the ozone layer in the stratosphere. At the time, CFCs were widely used as chemical propellants and refrigerants. Molina and Rowland followed up the short Nature paper with a 150-page report for the United States Atomic Energy Commission (AEC), which they made available at the September 1974 meeting of the American Chemical Society in Atlantic City. This report and an ACS-organized press conference, in which they called for a complete ban on further releases of CFCs into the atmosphere, brought national attention.
Rowland and Molinas findings were disputed by commercial manufacturers and chemical industry groups, and a public consensus on the need for action only began to emerge in 1976 with the publication of a review of the science by the National Academy of Sciences. Rowland and Molinas work was further supported by evidence of the long-term decrease in stratospheric ozone over Antarctica, published by Joseph C. Farman and his co-authors in Nature in 1985. Ongoing work led to the adoption of the Montreal Protocol (an agreement to cut CFC production and use) by 56 countries in 1987, and to further steps towards the worldwide elimination of CFCs from aerosol cans and refrigerators. By establishing this protocol, the amount of CFCs being emitted into the atmosphere decreased significantly, and while doing so, it has paced the rate of ozone depletion and even slowed climate change.  It is for this work that Molina later shared the Nobel Prize in Chemistry in 1995 with Paul J. Crutzen and F. Sherwood Rowland. The citation specifically recognized him and his co-awardees for "their work in atmospheric chemistry, particularly concerning the formation and decomposition of ozone."
Following this in 1985, after Joseph Farman discovered a hole in the ozone layer in Antarctica, Mario Molina led a research team to further investigate the cause of rapid ozone depletion in Antarctica. It was found that the stratospheric conditions in Antarctica were ideal for chlorine activation, which ultimately causes ozone depletion.