One overriding issue exacerbated the regional and economic differences between North and South: slavery. Resenting the large profits amassed by Northern businessmen from marketing the cotton crop, many Southerners attributed the backwardness of their own section to Northern aggrandizement. Many Northerners, on the other hand, declared that slavery – the "peculiar institution" that the South regarded as essential to its economy – was largely responsible for the region's relative financial and industrial backwardness.

As far back as the Missouri Compromise in 1819, sectional lines had been steadily hardening on the slavery question. In the North, sentiment for outright abolition grew increasingly powerful.  Southerners in general felt little guilt about slavery and defended it vehemently.  In some seaboard areas, slavery by 1850 was well over 200 years old; it was an integral part of the basic economy of the region.

Although the 1860 census showed that there were nearly four million slaves out of a total population of 12.3 million in the 15 slave states, only a minority of Southern whites owned slaves. There were some 385,000 slave owners out of about 1.5 million white families.  Fifty percent of these slave owners owned no more than five slaves.  Twelve percent owned 20 or more slaves, the number defined as turning a farmer into a planter.  Three-quarters of Southern white families, including the "poor whites," those on the lowest rung of Southern society, owned no slaves.

It is easy to understand the interest of the planters in slave holding.  But the yeomen and poor whites supported the institution of slavery as well. They feared that, if freed, blacks would compete with them economically and challenge their higher social status.  Southern whites defended slavery not simply on the basis of economic necessity but out of a visceral dedication to white supremacy.

As they fought the weight of Northern opinion, political leaders of the South, the professional classes, and most of the clergy now no longer apologized for slavery but championed it. Southern publicists insisted, for example, that the relationship between capital and labor was more humane under the slavery system than under the wage system of the North.

Before 1830 the old patriarchal system of plantation government, with its personal supervision of the slaves by their owners or masters, was still characteristic.  Gradually, however, with the introduction of large-scale cotton production in the lower South, the master gradually ceased to exercise close personal supervision over his slaves, and employed professional overseers charged with exacting from slaves a maximum amount of work.  In such circumstances, slavery could become a system of brutality and coercion in which beatings and the breakup of families through the sale of individuals were commonplace.  In other settings, however, it could be much milder.

In the end, however, the most trenchant criticism of slavery was not the behavior of individual masters and overseers.  Systematically treating African-American laborers as if they were domestic animals, slavery, the abolitionists pointed out, violated every human being's inalienable right to be free.