Barcelona have let go of the greatest player of all time and Real Madrid have lost a three-time Champions League-winning partnership – so is this defending champions Atletico Madrid’s title to lose?
Or could there be a new winner?
As the new La Liga season kicks off this weekend with fans being allowed back into games, BBC Sport looks at how the ‘big three’ are shaping up – and what else there is to watch out for.
Barca lose Messi… and may have more problems than that
Barcelona have one trophy – the Copa del Rey – to show for their last two seasons with Lionel Messi, and now they prepare for a season without their greatest player for the first time since 2003.
Barca’s financial problems, which led to them being unable to afford to keep their all-time top scorer even though he had accepted a 50% pay cut, stole all the headlines this week. He has since moved to Paris St-Germain.
But there are more ramifications than that to come, with the status of their new signings unclear.
There are doubts on whether they will be able to register Memphis Depay, Sergio Aguero, Eric Garcia or Emerson Royal – their four summer signings.
Barcelona have to register their final squad by 1 September – but are likely to need to move players on to be able to fit in their new signings under La Liga’s wage cap rules.
Ronald Koeman’s side have until Friday to register their squad for Sunday’s opener against Real Sociedad (19:00 BST).
Aguero’s injury – which will keep him out until the end of October – means there is no need to register him yet.
With so much uncertainty, how will their fans react now they are allowed back into the Nou Camp? This will be the first time there have been supporters in the stadium during the Koeman reign – and the team are in their worst state for years.
Having said that, Barcelona missed their fans last season. They fared better away from home in La Liga in 2020-21, with 41 points on their travels and 38 at the Nou Camp.
New manager, ‘new’ stadium, new defence for Real
Real Madrid are going to have a new look at the back this season after losing what has been their first-choice centre-back partnership of most of the past decade.
Sergio Ramos and Raphael Varane played together on 227 separate occasions for Real Madrid (W147 D43 L37) – including three Champions League finals.
Ramos left for Paris St-Germain this summer at the end of his Real contract, while Varane is set to join Manchester United for £34m.
David Alaba is likely to take the place of one of them, despite only playing about a quarter of his career games at centre-back. The Austria international is their only summer signing to date, joining on a free transfer from Bayern Munich.
On top of that, they have Carlo Ancelotti back in charge after the exit of Zinedine Zidane. Ancelotti led Real to the 2013-14 Champions League (with Ramos and Varane at the back) and Copa del Rey.
It is now four years, though, since he won a trophy after undecorated spells with Napoli and Everton.
On top of that, they are hoping to be back at the Bernabeu – which is still being redeveloped – by the fourth round of games, after starting off with three away games.
They have played at the Estadio Alfredo di Stefano, based at their training centre, for the entire coronavirus pandemic.
Oh, and Gareth Bale is back at the club, following his loan stint at Tottenham. How will his season pan out, in what is the final year of his Real contract?
Can Atletico Madrid retain title?
No team other than Barcelona or Real Madrid have retained the La Liga title since Athletic Bilbao in 1984.
Atletico Madrid have that chance after beating Real Madrid to the title last season by two points.
They come into the season with mostly the same squad as last season – with midfielders Rodrigo de Paul and Marcos Paulo coming in with just some of last season’s loan players plus Vitolo leaving.
That consistency could be key. Diego Simeone has signed a new three-year deal to stay in charge, having led them to two of the past eight titles.
Atletico Madrid handled the lack of fans the best, finishing top of the home form table (as well as the actual table) with 48 points from 19 games – compared with 38 points on the road.
Can anyone else win La Liga?
Sevilla would appear to be the next best-placed team to win the title – having finished fourth last season under Julen Lopetegui.
Erik Lamela has come in from Tottenham to boost their squad – but he and goalkeeper Marko Dmitrovic are their only signings.
Will that alone be enough to bridge the nine-point gap on Atletico? The bookmakers make them 20-1 fourth favourites.
Further down the table, no other contenders jump out. Only four teams – Real, Valencia, Getafe and Granada – have changed manager with not many eye-catching transfers either.
Europa League winners Villarreal finished seventh last term, but their biggest summer signing, Juan Foyth, was already there on loan last season.