Nestling on the western shores of Lough Neagh, Mid-Ulster is a mostly rural constituency made up of lots of country villages and main towns like Cookstown, Magherafelt and Coalisland.
It's an area traditionally dominated by the Sinn Féin vote, with Mr McGuinness having first taken the seat in 1997 and since built up a majority of over 15,000.
The only constituency where the party has a bigger majority is West Belfast.
But Mr McGuinness stepped down as part of his party's policy of phasing out double-jobbing, paving the way for the seat to be contested by his colleague Francie Molloy - who is also a sitting MLA.
He's confident of a win, but wary of complacency.
"The problem with by-elections is getting people out," Mr Molloy told UTV.
"We want to maximise the vote, we want to continue the service we've been providing in Mid-Ulster - and to do that, we need to get the turn-out."
It's a four-way contest and Sinn Féin is widely expected to retain the seat. But while the outcome has been predicted - it's still an interesting race ...
Tracey Magee, UTV
Unionist hopes of securing the seat, which they lost when the boundaries were redrawn in 1995, are resting with joint DUP and UUP candidate Nigel Lutton.
He lost his father, a former RUC reservist, when he was murdered by the IRA in 1979.
But Mr Lutton has been keeping a low profile ahead of the election and wasn't available for interview by UTV.
When he lodged his nomination papers over a week ago, he said: "It's about cooperation.
"And I think if we can give confidence to unionists, and particularly young unionists, it would take politics from the street and into a peaceful means of moving forward."
Some, including the Alliance candidate Eric Bullick, fear that an agreed unionist candidate will entrench the electorate. He feels 'bread-and-butter issues' are more important.
"People tell me that, in the short term, what they're struggling with is how to fill the oil bill," he said.
"And, in the long term, what they're struggling with is how to maybe get jobs for their children."
The SDLP candidate Patsy McGlone, who is a high profile member of his party, is hoping to be a credible choice.
He says that the selection of a joint unionist candidate has distracted from the everyday concerns he's hearing about on the doorsteps.
Mr McGlone told UTV: "What people are saying is: 'We're not really interested in sham fights or sectarian headcounts - nor are we interested, on the other side, in border polls and flag disputes.'
"What they're saying, very clearly, is what this election should be about is the future. Jobs, stability, giving people a better future."
As well as determining the new MP for the area, the result of the by-election in Mid-Ulster could also decide the future of unionist electoral strategy.