The immediate issue is NATO's planned training and advisory mission in Afghanistan after it ends its biggest ever combat operation there next year, clearing the decks for leaders to set a new course for the alliance at a summit in late 2014.
Officials say the focus of the two-day meeting in Brussels is to build on NATO's active military role since the early 1990s, from the Balkans to Afghanistan and Libya, safeguarding gains in inter-operability and capability at a time when defence budgets are under strain.
The aim is a NATO which remains relevant and effective in a changing world where the challenges are as much military as political and economic, threatening to boil over into conflict and social upheaval.
"We have got to ensure that we sustain NATO's military edge," a senior US official said.
"In the context of extreme budgetary constraints... It is incumbent on us all to do more with (the money) that we have."
The 28 allies, plus NATO's partners and sometimes adversaries such as Russia, will review issues such as how to destroy Syria's chemical weapons arsenal.
Missile defence, a hugely sensitive issue for Moscow, is on the agenda given US and European concerns of a threat from Iran despite the recent signing of an initial deal on its contested nuclear programme.
Relations with Ukraine and Georgia provide another difficult issue for Russian Foreign Minister Sergei Lavrov and his US counterpart Secretary of State John Kerry as NATO seeks to maintain and boost ties with former Soviet states.
Continued and growing protests in Ukraine after the government ditched a planned association accord with the EU are likely to test ties.
Following the NATO meeting, Kerry will travel to Moldova which did sign up with Brussels last week despite intense Russian pressure not to.
"We are making this brief stop to demonstrate US support for the important choice that Moldova made," the US official said.
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