When speaking about the first half of the nineteenth century, the history of sectarian division between North and South really tends to revolve around the problem of slavery. One of the key turning points in this history was the invention of the cotton gin in 1793, which greatly increased slavery's economic viability. This had the effect of making slavery as an institution far more strongly entrenched within Southern society than it had been even a generation earlier. Meanwhile, in the North, abolitionism (with its uncompromising moral condemnation of slavery) was gradually taking root as well and would become more strongly established over time. Thus, it was the subject of slavery as well as this discourse that surrounded it which really drove the growing division between North and South.
We see this issue coming to the forefront as early as 1819 with the Missouri Crisis. Even this early in US history, there was already an awareness that the subject of slavery would ultimately be decided politically and would therefore hinge on the balance of power between slave states and free states. Thus, when Missouri applied for statehood in 1819 (as a slave state), which would have disrupted the balance between the slave states and free states, it caused uproar among northerners, who were concerned about the political implications. This controversy was mitigated by the Missouri Compromise, which saw Maine and Missouri both join the Union, thus maintaining equilibrium.
The reality, however, was that this solution was always going to be a precarious one. As the country continued to expand, it was understood that those territorial acquisitions would eventually result in the creation of new states (which would eventually have the potential for disrupting this political balance of power). This is what proceeded to happen in the 1840s, when the US underwent a dramatic era of geographic expansion, one which unleashed a political crisis in the 1850s. This series of confrontations originated in 1849 with California's application for statehood and would lead to the Civil War.