The Three Lions will endeavour to secure top spot in the group and seal progress to next winter's tournament, whereas San Marino - as ever - are simply playing for pride.
Having already led England to a World Cup semi-final, and with a plethora of talented youngsters at his disposal, many are backing Gareth Southgate's current crop to end their barren trophyless spell this summer.
This year's European Championships represents a magnificent opportunity for England to stake their claim as one of the world's best, and while their squad for the upcoming World Cup qualifiers is talented enough, the prospect of more top internationals returning from injury in time for this summer's tournament will certainly have tongues wagging.
For now, though, Southgate's Three Lions must simply focus on the task at hand in Group I - where top spot is certainly not guaranteed in a group with Robert Lewandowski's Poland - but the visit of San Marino gives the hosting manager the chance to experiment with some of his less experienced players and hopefully lay down a marker for the rest of the month.
However, England's Nations League campaign was hardly an ideal warm-up for their qualification period, as defeats to Denmark and Belgium - whom they also managed to beat at Wembley - saw them finish third in League A Group 2, although they did manage to ease past neighbours Wales and the Republic of Ireland in friendlies last autumn.
Furthermore, England's dismal defeat to Denmark represents their only defeat on home soil in their last 12 matches - with the other 11 all ending in victory - so San Marino will certainly not harbour aspirations of a gargantuan shock as they prepare to travel to the capital.
With a whopping 206 places separating England from San Marino - the worst-ranked team in the world - in the FIFA standings, this week's visitors to Wembley will just want to give a good account of themselves in a group that is likely a forgone conclusion for the microstate.
After losing a whopping 40 games in a row across all competitions, Franco Varrella's side managed to pick up two points in their Nations League campaign after holding Gibraltar and Liechtenstein to goalless stalemates, but their agonising wait for a win goes on and they finished rock bottom of League D Group 2 last year.
However, by amassing two points in their group, San Marino set a national record for the most points ever collected in a major tournament, and those two successive goalless stalemates also represented the first time ever that the 210th-ranked side had gone back-to-back games unbeaten.
On the other hand, San Marino have not managed to avoid defeat in a World Cup qualification game since holding Latvia to a 1-1 draw in 2001 - after which Gary Johnson immediately resigned from his Latvia post - and England fans would certainly be calling for Southgate's head if Varrella's men could inexplicably defy the odds at Wembley this week.
Davide Gualtieri famously took just 8.3 seconds to open the scoring against England for San Marino - a game which the Three Lions ultimately won 7-1 - and this week's hosts have scored at least five goals in all of their six victories over the microstate, most recently prevailing 6-0 in 2015.
England's attack has been depleted following injuries to Jack Grealish, Jadon Sancho, Tammy Abraham, Harvey Barnes and Danny Ings, but the uncapped Ollie Watkins will hope to earn his first start for the national team here, especially with Marcus Rashford out of contention.
Indeed, this game gives Southgate the chance to call upon some up-and-coming starlets, so the likes of Phil Foden and Jude Bellingham - who has been cleared to link up with the team - are both in line for starts, but Bukayo Saka and Kyle Walker have both been ruled out.
San Marino's mix of professionals and part-timers includes only three players who have ever found the back of the net for the country - Matteo Vitaioli, Filippo Berardi and Mirko Palazzi - and all three could line up at Wembley this week.
England possible starting lineup:
Henderson; Coady, Mings, Dier; James, Phillips, Bellingham, Shaw; Mount, Foden; Watkins
San Marino possible starting lineup:
E. Benedettini; Battistini, Brolli, Simoncini, Palazzi; Gasperoni, Golinucci; Tomassini, Berardi, Vitaoli; Nanni
We say: England 6-0 San Marino
This may simply be a case of how many goals England can chalk up over the course of 90 minutes, and Southgate's youngsters will be determined to stake their claims for spots in the Euros squad this summer. A convincing victory in their inaugural game is no less than the Three Lions faithful will expect this week, and we can see Southgate's side hitting San Marino for six in the capital.