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Roy (Woody Harrelson) og Jessie (Emily Mortimer) er det perfekte amerikanske par, som er på rejse fra Beijing til Moskva på den legendariske Transsibiriske ekspres. De bliver venner med et andet par, Carlos (Eduardo Noriega) og Abby (Kate Mara), som ikke er, hvad de fremstår som. Ufrivilligt bliver Roy og Jessie blandet ind i transport af stoffer og morderisk bedrag, da alle fire bliver mål for den tidligere KGB agent Grinkos (Ben Kingsley) efterforskning.
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