The Durham-Humphrey Amendment explicitly defined two specific categories for medications, legend (prescription) and over-the-counter (OTC). This amendment was co-sponsored by senator Hubert H. Humphrey Jr., who was a pharmacist in South Dakota before beginning his political career. The other sponsor of this amendment was Carl Durham, a pharmacist representing North Carolina in the House of Representatives.

The bill requires any drug that is habit-forming or potentially harmful to be dispensed under the supervision of a health practitioner as a prescription drug and must carry the statement, "Caution: Federal law prohibits dispensing without a prescription."  The bill also requires that all drugs have adequate directions for use.

Prior to the enaction of this law, there was no requirement that any drug be labeled for sale by prescription only. The amendment defined prescription drugs as those unsafe for self-medication and which should therefore be used only under a doctor's supervision.

Legend drugs can only be dispensed with direct medical supervision whereas OTC drugs can be purchased and used without a prescription. This law also allows for new prescriptions to be called in over the phone and refill authorized over phone.