No one is precisely certain of the cause of CCD. A January 2010 Congressional Report, entitled "Honey Bee Colony Collapse Disorder" identified three major possibilities: pesticides, parasites, and a combination of existing stresses that may compromise the immune system of bees and disrupt their social system.

Many environmental groups and publications have honed in on the risks posed by pesticides, and in particular a class of pesticides known as neonicotinoids. One such pesticide, clothianidin, is "highly toxic to honey bees" according to an Environmental Protection Agency (EPA) Fact Sheet and has already been banned in several European countries. The Natural Resources Defense Council (NRDC) and the Xerces Society successfully sued to invalidate EPA approval of the pesticide spirotetramat, a related neonicotinoid pesticide, in December of 2009, but other neonicotinoids like clothianidin remain on the shelves.