Now five years into their dynasty, the Panthers are facing the biggest challenge since making a 1-3 start to the season.
Still early in the season, Friday night's clash with North Queensland suddenly looms as crucial with halfback Nathan Cleary returning from a concussion.
For years the focus has been on the big names Penrith have lost, from Viliame Kikau to Stephen Crichton and Jarome Luai.
It is the kind of 17 that would be good enough to fight for a premiership, and would almost certainly play finals football.
The Panthers have also lost experienced coaches Cameron Ciraldo (Bulldogs), Trent Barrett (ex-Bulldogs and current Brisbane assistant) and Andrew Webster (Warriors).
But the biggest challenge for the Panthers could well be what lies beneath in their lower leagues, as they can no longer depend on ready-made replacements when injuries or departures hit.
It was only three seasons ago Penrith created history when they won the NRL, NSW Cup, Jersey Flegg and under-19s, while reaching the under-17s grand final.
That lower-grade and junior system has also been raided by rivals, who are providing more money and greater opportunities.
Penrith have over the years lost at least 30 players - a full NRL roster - whom they wanted to keep in their ranks but were unable to.
One prime example is Dolphins halfback Isaiya Katoa, who many at Penrith considered one of their most talented juniors.
Parramatta's first-choice fullback Isaiah Iongi and this week's hooker Ryley Smith were also recruited from Penrith's lower grades.
J'maine Hopgood is another, with the Eels lock now a State of Origin star.
Cronulla's back-up No.1 Liam Ison is another who sought a future elsewhere, while the Dolphins launched an assault when they entered the competition.
When put together, the 30-player roster still capable of featuring in the NRL today does not include veterans James Tamou and Josh Mansour.
The Panthers have responded by unearthing rising stars Casey McLean, Liam Henry, Lindsay Smith and Jack Cole, with only nine players from the 2021 premiership-winning side featuring in last year's fourth-straight grand final.
Penrith coach Ivan Cleary last week brushed off the depth challenge, joking it was unlikely anyone would be crying too much for the four-time premiers.
Nathan Cleary reiterated his dad's words, with Penrith now streamlining their training program from the NRL down to under-17s.
"I still believe that our depth is great," the halfback said.
"I'm very confident with any player that comes in and plays first grade because we've been able to build these systems.
"These young guys train from such a young age so once they come into first grade they actually know what we're doing and fit in really seamlessly."
PENRITH'S LOST ROSTER:
PLAYERS: Starting side: Stephen Crichton, Charlie Staines, Paul Momirovski, Brent Naden, Sunia Turuva, Matt Burton, Jarome Luai, James Fisher-Harris, Api Koroisau, Spencer Leniu, Kurt Capewell, Viliame Kikau, J'maine Hopgood.
Bench: Jack Cogger, Zane Tetevano, Zac Hosking, Jack Hetherington. 18th: Jaeman Salmon.
Reserves: Jed Cartwright, Jett Cleary, Robert Jennings, Niwhai Puru, Hohepa Puru, Isaiah Iongi, Isaiya Katoa, Sean O'Sullivan, Liam Ison, Ryley Smith, Mason Teague, Keagan Russell-Smith.
COACHES:
Cameron Ciraldo (Bulldogs), Trent Barrett (ex-Bulldogs and current Brisbane assistant) and Andrew Webster (Warriors).
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