He was part of the Spain squad for the 2006 FIFA World Cup and made one appearance in their victorious UEFA Euro 2008 campaign, earning him his first international honour.

[6] On 31 October 2001, he made his UEFA Champions League debut in Barcelona's 1–0 group stage win against Fenerbahçe at Camp Nou.

Reina made his Liverpool debut against Total Network Solutions, now known as The New Saints, in the first qualifying round for the 2005–06 UEFA Champions League.

For the 2005–06 season, Reina took over as Liverpool's first-choice goalkeeper, relegating 2005 UEFA Champions League final hero Jerzy Dudek to the bench.

Reina's run ended at eight league games, when James Beattie scored for Everton in Liverpool's 3–1 Merseyside derby win on 28 December 2005.

On 5 February 2006, in a Premier League match against Chelsea, Reina, having made a challenge on Eiður Guðjohnsen moments earlier, was sent off for violent conduct against Arjen Robben.

During the 2006–07 season, Reina's status as Liverpool's number-one goalkeeper was further cemented after Jerzy Dudek conceded nine goals within a week in two cup ties against Arsenal.

[citation needed] Three weeks later in Athens, Reina became only the third player to follow in his father's footsteps by appearing in a European Cup final.

[20] On 17 October 2009, Liverpool were beaten 1–0 by Sunderland with a goal from Darren Bent, which was deflected past Reina via a beach ball thrown from the crowd.

[22] Reina got his 2010–11 season off to a poor start, with a late own goal to give Arsenal a 1–1 draw in Liverpool's opening Premier League fixture.

Manager Roy Hodgson, club captain Steven Gerrard and vice-captain Jamie Carragher were all quick to get behind Reina and back him to not let the mistake affect his season.

[23][24] Reina captained the team in Europa League matches against Napoli and Steaua București due to the absences of Steven Gerrard and Jamie Carragher.

[29] On 29 November 2011, Reina broke the club record for most clean sheets in a 2–0 Football League Cup quarter-final win over Chelsea.

[30] On 26 February 2012, Reina won his second major honour with Liverpool, beating Cardiff City on penalties in the 2012 League Cup final.

[33] He missed Premier League matches against Aston Villa and Blackburn Rovers, as well as the FA Cup semi-final against Everton on 14 April.

[35] On 30 August 2012, Reina made a mistake in a 1–1 draw against Hearts in the Europa League to give the Edinburgh club the lead at Anfield.

[39] As a result, on 29 July 2013 Reina completed a loan move to Serie A side Napoli, reuniting him with former Liverpool manager Rafael Benítez.

[49] His appearance in that match meant that he became the first goalkeeper and Spaniard in history to play in four of Europe's top leagues: Spain, England, Italy, and Germany.

[50][51][52] On 9 May, as Bayern had already won the 2014–15 Bundesliga and had a Champions League semi-final second leg against Barcelona to come, regular goalkeeper Manuel Neuer was rested for their home match against FC Augsburg and Reina started.

He was given a straight red card after 14 minutes when he conceded a penalty with a foul on Raúl Bobadilla; Neuer came on in place of Philipp Lahm but Paul Verhaegh hit the post for Augsburg, which eventually won 1–0.

[63] He made his league debut with the team on 2 April 2019, coming on as a substitute for Donnarumma in a 1–1 home draw against Udinese, following the latter's injury in the opening ten minutes of play.

[57] In the first half of his second season with the club, he continued to serve as a back-up to Donnarumma, and only made once appearance for the team, which came in a 2–1 away win over Genoa in Serie A on 5 October 2019; during the match, Reina was at fault for the opening goal, as he had misjudged Lasse Schone's free kick, but he later saved a penalty against the same opponent, which he himself had conceded, in stoppage time.

[64][65] On 13 January 2020, Reina joined Premier League side Aston Villa on loan for the rest of the 2019–20 season; after the team's usual first choice goalkeeper Tom Heaton was ruled out through injury until the summer.

[75] Reina made his debut on 17 August 2005, keeping a clean sheet in a 2–0 friendly win over Uruguay at El Molinón in Gijón.

His sole appearance was in the last group game in Bloemfontein, keeping a clean sheet in a 2–0 win over hosts South Africa, a result which was a world record 15th consecutive international victory for Spain.

[93] He has set a number of goalkeeping records for Liverpool and won the Premier League Golden Glove award in his first three seasons at the club.

[95] Reina married his longtime girlfriend Yolanda Ruiz in Córdoba on 19 May 2006,[96] before joining up with the Spain national squad for the 2006 World Cup.

[98][99] Although a steely and serious figure as goalkeeper, Reina is known for his exuberant, jester-like character off the pitch, often entertaining his teammates with jokes and songs,[100][101] and famously acting as a crowd-pleasing master of ceremonies at Spain's official victory celebrations following the 2008 European Championship,[102] the 2010 World Cup[103] and Euro 2012.

[104] In March 2020, he tested positive for COVID-19;[105] later that month, in an interview with Spanish radio station COPE, he announced that he had made a "full recovery".

[108] In May 2020, Reina drew attention for supporting the anti-lockdown protests by national conservative political party Vox amidst the COVID-19 pandemic in Spain.