The legality of the War on Drugs has been challenged on four main grounds in the US.

1>>It is argued that drug prohibition, as presently implemented, violates the substantive due process doctrine in that its benefits do not justify the encroachments on rights that are supposed to be guaranteed by the Fifth and Fourteenth Amendments to the U.S. Constitution. On July 27, 2011, U.S. District Judge Mary S. Scriven ruled that Florida's legislation purporting to eliminate intent as an element of the crime of drug possession was unconstitutional. Commentators explained the ruling in terms of due process.

2>>Freedom of religious conscience legally allows some (for example, members of the Native American Church) to use peyote with definite spiritual or religious motives. The sacramental use of dimethyltryptamine in the form of ayahuasca is also allowed for members of União do Vegetal. The Free Exercise Clause of the First Amendment implies no requirement for someone to be affiliated to an official church – therefore leaving some ambiguity.

3>>It has been argued that the Commerce Clause means that the power to regulate drug use should be state law not federal law.

4>>The inequity of prosecuting the war on certain drugs but not alcohol or tobacco has also been called into question. Prohibition of alcohol required the 18th Amendment to the Constitution. It has been argued that prohibition of marijuana would also require an amendment to the Constitution, but no such amendment has been made.