It is also the first time in nearly a decade that a launch with astronauts will take place on US soil, with lift-off scheduled for 4.33pm local time from Nasa's Kennedy Space Center in Cape Canaveral, Florida,
But more than 6,000km away in the UK, clear skies will mean people will also be able to catch the Falcon 9 rocket soar overhead.
Weather permitting, sky gazers in the UK will be able to view the SpaceX rocket at around 9.55pm by looking south-west.
The International Space Station (ISS), where the astronauts are headed, will also be visible at around 11pm. It is possible to track it in real-time using a tool developed by the European Space Agency.
A 2019 survey by YouGov found that only 32 per cent of British people thought private companies should take astronauts to the ISS.
The same poll found that half of Britons would not take a trip to the moon, even if their safe return was guaranteed.
SpaceX eventually hopes to take tourists into space, with CEO Elon Musk hoping the first flights will take place as early as 2021.
Tickets cost $55 million for a 10-day trip to the ISS and back, which if successful could herald a new era of space tourism.
Wednesday's launch might be in doubt, due to poor weather at the launch site. If it is delayed, another launch window is being prepared for Saturday.
Coverage of the launch is being live streamed on Nasa's YouTube channel.
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