Smith's first two games for Melbourne were during the 2002 NRL season, both played at half-back. The following year he played as the Storm's hooker. In 2003 the Queensland rugby league team were without a specialist hooker. After experimenting with different players in the position for the first two matches of the 2003 State of Origin series and losing both, Smith was named at hooker for the third match (and for the next six years no other player would wear the number 9 for the Maroons until this run of 19 consecutive Origins was cut due to injury). He was named the Melbourne Storm's rookie of the year in 2003.
In 2005 Smith was named the Melbourne Storm's player of the year. The following year he first represented Australia and won the Dally M Medal. In addition he was again named the Storm's player of the year. Smith led the storm to the 2006 NRL Grand Final. While the game was still in the balance he was forced from the field with injury, which the Storm's loss has been largely attributed to.
Cam Smith on international duty with the Kangaroos in 2006
Smith became regular captain of the Melbourne Storm in 2008. Smith captained the Maroons for the entire 2008 State of Origin series due to the absence of regular captain Darren Lockyer. The Maroons won the series with him as the skipper, despite losing the first match 18-10. In August 2008, Smith was named in the preliminary 46-man Kangaroos squad for the 2008 Rugby League World Cup, and in October 2008 he was selected in the final 24-man Australia squad. Cameron was suspended for two weeks in the 2008 finals series after a grapple tackle on Brisbane's Sam Thaiday. The suspension would have only been one week had he not had carry over points from a previous grapple tackle in round 1 of the year's competition. This meant he was suspended for Melbourne's 2008 grand final. Melbourne Storm CEO Brian Waldron and coach Craig Bellamy claimed the judiciary had made their minds up before Cameron's case was heard. The judiciary panel members then threatened to sue the club if the comments were not retracted. Cameron signed a four-year extension to his contract in December 2008, resulting in him being a contracted player through to the end of at least the 2012 season. His contract is rumoured to be partly funded by third party sponsors who do not contribute to the standard salary cap. He became the Melbourne Storm's most experienced playing player due to the retirement of Matt Geyer at the end of 2008. He became the last current Storm player in the squad who played under Mark Murray as well as the only one to have played in a season when the Storm did not make the finals due to their performance (the Storm finished 10th in 2002, the year Smith made his debut).
In April 2009, he was named in the preliminary 25 man squad to represent Queensland in the opening State of Origin match for 2009. He was selected for Australia in the one-off test match against New Zealand on 8 May 2009. In the preliminary final in which Melbourne defeated the Brisbane Broncos 40–10, he became Storm's highest ever point scorer, beating Matt Orford's record of 877. Smith led the Storm in their 2009 NRL Grand Final victory over the Parramatta Eels. At the end of the season he joined the Kangaroos on their campaign to win the 2009 Four Nations tournament in England. He scored the try that saved Australia from losing in the opening match and also scored in the Kangaroos' victory against England in the final.
Smith was named man-of-the-match in Queensland's win in Game I and later Game III of the 2011 State of Origin series, subsequently resulting in his naming as the Wally Lewis medal winning man-of-the-series. On 3 November 2011 The annual RLIF Awards dinner was held at the Tower of London and Smith was named Hooker of the year.
Smith has three children with his long term partner Barbara Johnson, whom he married in late 2011: a daughter, Jada, who was born in 2008; a son, Jasper, who was born the following year; and a second daughter, Matilda born in 2013.