Karan Kapoor (Saif Ali Khan) who works as a cartoonist with one of India's leading newspapers. Karan runs a cartoon strip in the paper under the name of Hum Tum. He sees the world is divided by Boy and Girl, not by country, not by religion. It's the only divison Karan sees in this world.
Karan met Rhea (Rani Mukerjee) for the first time in Amsterdam. There they disagreed on everything. So to put things right, Karan innocently kissed her to confirm their friendship. But things went worse and the meeting ended on a bad note. Six months later, they again meet in New York, the Amsterdam kiss is still fresh in Rhea's mind and she spills the beans to Karan's steady girlfriend.
From then he meets Rhea on a regular basis at various stages in their lives. But every meeting has ended on a bad note. During this period, Rhea has gone through some personal tragedies and also passed several ups and downs but Karan has always been there for her. During this time she has moved all over the place, from Mumbai to Paris to New York and back to Mumbai. Karan even tried fixing her up with a friend of his - with her mothers permission of course - but as with everything else, this didn't quite work out either.
As luck would have it, Karan's career as a cartoonist was soaring and so one thing led to another and Rhea took off once again on a bad terms.
But despite their mishaps, destiny has bigger plans for Karan and Rhea......