Shadow business secretary John Denham and shadow health secretary John Healey have stepped down from their posts ahead of a reshuffle by Ed Miliband of his Labour top team.
Their departures are expected to pave the way for Mr Miliband to bring some new blood into the shadow cabinet from the 2010 intake of MPs.
Mr Denham will instead now serve as Mr Miliband's unpaid parliamentary private secretary.
In his resignation letter, dated September 30, Mr Healey said that he wants to spend more time with his family.
"My family have accepted this for over a decade, and supported me throughout," he said. "But for now, I want to be able to give them more during the last couple of years we have left while our son is still with us at home. It is time for me to put them first."
In his reshuffle, Mr Miliband will for the first time have a complete free hand in picking his top team following a rule change which means the shadow cabinet is no longer elected by Labour MPs.
Former deputy prime minister Lord Prescott has urged Mr Miliband to take the opportunity to get rid of ineffective frontbenchers, saying there are some who are "undoubtedly not carrying their weight".
Among the newcomers from the 2010 intake of MPs, shadow work and pensions minister Rachel Reeves is being strongly tipped for a place in the top team.
However, speculation about a possible frontbench return for former cabinet "big beasts" Alan Johnson and Lord Falconer is being played down at Westminster.
Shadow chancellor Ed Balls, shadow home secretary Yvette Cooper and shadow foreign secretary Douglas Alexander are among those expected to retain their current portfolios.