The history of large-scale slavery in the State of Missouri began in 1720, when a French entrepreneur named Philippe François Renault brought about 500 negro slaves from Saint-Domingue up the Mississippi River to work in lead mines in what is now southeastern Missouri and southern Illinois. These people were the first enslaved Africans brought en masse to the middle Mississippi River Valley. Prior to Renault's enterprise, slavery in Missouri under French colonial rule had been practiced on a much smaller scale as compared to elsewhere in the French colonies.
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The institution of slavery only became especially prominent in the area following two major events: the invention of the cotton gin by Eli Whitney in 1793, and the Louisiana Purchase in 1803. These events led to the westward migration of slave-owning settlers into the area of present-day Missouri and Arkansas, then known as Upper Louisiana. The majority of slave owners in Missouri had moved from worn-out agricultural lands in North Carolina, Tennessee, Kentucky, and Virginia. Still, cotton cultivation, arguably the industry to which slave labor was the most important, was never as well-suited to Missouri's climate as to the rest of the southern United States, and was limited entirely to the most southern parts of the state near the border with present-day Arkansas. Slavery in other areas of Missouri was concentrated in other agricultural industries, such as those for tobacco, hemp, grain, and livestock. A number of slaves was also hired out as stevedores, cabin boys, or deck hands on the ferries of the Mississippi River.
By the beginning of the American Civil War, only 36 counties in Missouri had 1,000 or more slaves. Male slaves fetched a price of up to $1,300.  In the State Auditor's 1860 report, the total value of all slaves in Missouri was estimated at approximately US $44,181,912.
Missouri's territorial slave code was enacted in 1804, a year after the Louisiana Purchase, under which slaves were banned from the use of firearms, participation in unlawful assemblies, or selling alcoholic beverages to other slaves. It also severely punished slaves for participating in riots, insurrections, or disobedience of their masters. It also provided for punishment by mutilation of a slave who sexually assaulted a white woman; a white man who sexually assaulted a female slave of another white man was typically charged with nothing more than trespassing upon her owner's property. The code was retained by the State Constitution of 1820.
At the end of 1824, the Missouri General Assembly passed a law providing a process for enslaved persons to sue for freedom and have some protections in the process. An 1825 law passed by the General Assembly declared blacks incompetent as witnesses in legal cases which involved whites, and testimonies by black witnesses were automatically invalidated. In 1847, an ordinance banning the education of blacks and mulattoes was enacted. Anyone caught teaching a black or mulatto person, whether enslaved or free, was to be fined $500 and serve six months in jail.
Elijah Lovejoy edited an abolitionist newspaper, the Observer, in St. Louis before being driven out by a mob in 1836. He fled across the Mississippi River to Alton, Illinois, where he was later killed in an exchange of gunfire with a pro-slavery mob.
In 1846, one of the nation's most public legal controversies regarding slavery began in St. Louis Circuit Court. Dred Scott, a slave from birth, sued his owner's widow on the basis of a Missouri precedent that held that slaves freed through prolonged residence in a free state or territory would remain free upon returning to Missouri. Scott had spent several years living in Illinois and the Wisconsin Territory with his owner, Dr. John Emerson, before returning to Missouri in 1840. After Emerson's death, Emerson's widow refused to buy Scott's and his family's freedom, so Scott resorted to the legal action permitted him under Missouri's 1824 law.
Scott eventually lost his case in the Missouri Supreme Court, but brought legal suit again in 1853 under federal law. The case was appealed to the United States Supreme Court and became a flashpoint in the ongoing national debate over the legality of slavery. In 1857, the Supreme Court handed down its verdict in Dred Scott v. Sandford: slaves were not citizens, and therefore Scott did not have the right to sue for his family's freedom. The landmark decision found the provisions of the Missouri Compromise of 1820 unconstitutional, and helped to fan the flames of conflict between pro-slavery and anti-slavery factions in the United States. The Scott family was eventually granted freedom by their owners, but Scott died shortly after, in 1858.
As one of the border states during the American Civil War, Missouri was exempt from President Abraham Lincoln's 1863 Emancipation Proclamation decreeing the freedom of slaves in all territory then held by Confederate forces. On January 11, 1865, a state convention approved an ordinance abolishing slavery in Missouri by a vote of 60-4,  and later the same day, Governor Thomas C. Fletcher followed up with his own "Proclamation of Freedom".  This action effectively marked the end of legal slavery in the state of Missouri.
- Marguerite Scypion, a slave of African and Native American descent who sued for her freedom
- Missouri Constitutional Convention of 1861-1863
- Federal Reserve Bank of Minneapolis Community Development Project. "Consumer Price Index (estimate) 1800–". Federal Reserve Bank of Minneapolis. Retrieved January 2, 2018.
- Missouri (1865). Journal of the Missouri state convention, held at the city of St. Louis January 6-April 10, 1865. St. Louis: Missouri Democrat. pp. 25–26. Retrieved 7 April 2016.
- Fletcher, Thomas C. (1865). Missouri's Jubilee. Jefferson City, MO: W. A. Curry, Public Printer. Retrieved 7 April 2016.