There are all sorts of elected positions on ballots but the main focus is on Congress, which is made up of the House of Representatives (lower house) and the Senate (upper house). Both are currently controlled by the Republican Party.
All 435 seats in the House are up for re-election and 35 Senate seats are in play, as are almost 40 governorships and the balance of power in virtually every state legislature.
Midterm elections indirectly represent a referendum on the president and his administration. Historically, the president's party tends to lose: of the 21 midterms held since 1934, the leading party has only made gains three times in the House and five times in the Senate.
Two years after an election that proved polls and prognosticators wrong, nothing is certain on the eve of the first nationwide elections of the Donald Trump presidency.
There are indications that an oft-discussed "blue wave" may help Democrats seize control of the lower house, a sprawling battlefield extending from Alaska to Florida. Most top races, however, are set in America's suburbs where more educated and affluent voters in both parties have soured on Trump's turbulent presidency, despite the strength of the national economy.
Democrats need to flip 23 Republican-held seats to claim the 218 majority.
Should Democrats win control of the House, as strategists in both parties suggest is likely, they could derail Trump's legislative agenda for the next two years. Perhaps more importantly, they would also win subpoena power to investigate the president's many personal and professional missteps.
Democrats face a far more difficult challenge in the Senate, where they are almost exclusively on defence in rural states where Trump remains popular.
In the 100-seat Senate the current balance of power is very tight, with Republicans holding a narrow 51-49 majority. To have control of the Senate, Democrats need to gain at least two seats.
Democratic Senate incumbents are up for re-election, for example, in North Dakota, West Virginia, and Montana — states Trump carried by 30 percentage points on average two years ago.
Tuesday's elections will also test the strength of a Trump-era political realignment defined by evolving divisions among voters by race, gender and especially education.
Trump's Republican coalition is increasingly becoming older, whiter, more male and less likely to have a college degree. Democrats are relying more upon women, people of colour, young people and college graduates.
A nationwide poll released Sunday by NBC News and The Wall Street Journal details the depth of the demographic shifts.
Democrats led with likely African-American voters (84 percent to 8 percent), Latinos (57 percent to 29 percent), voters between the ages of 18-34 (57 percent to 34 percent), women (55 percent to 37 percent) and independents (35 percent to 23 percent).
Among white college-educated women, Democrats enjoy a 28-point advantage: 61 percent to 33 percent.
On the other side, Republicans led with voters between the ages of 50 and 64 (52 percent to 43 percent), men (50 percent to 43 percent) and whites (50 percent to 44 percent). And among white men without college degrees, Republicans led 65 percent to 30 percent.
Former US president Barack Obama seized on the differences between the parties in a final-days scramble to motivate voters across the nation.
"One election won't eliminate racism, sexism or homophobia," Obama said during an appearance in Florida. "It's not going to happen in one election. But it'll be a start."
Trump has delivered a very different closing argument, railing against Latin American immigrants seeking asylum at the US border.
With the walking caravan weeks away, Trump dispatched more than 5,000 troops to the region. The president also said soldiers would use lethal force against migrants who throw rocks, before later reversing himself.
Still, his xenophobic rhetoric has been unprecedented for an American president in the modern era: "Barbed wire used properly can be a beautiful sight," Trump told voters in Montana.
The size of some states, the high number of absentee ballots, the predicted high turnout at the polls, and the expected closeness of some of the races all mean that many results won’t come out until the small hours of Wednesday morning at the earliest.
But given that some key districts should be called relatively early in the evening, we could have an idea of who will control the House by midnight.