With reference to UserInterfaceDesign there are perhaps two senses of this term. A weak sense, which means something along the lines of "not what I'm used to, therefore requiring effort to become proficient". This is the Heideggerean distinction between a tool being ready-to-hand versus present-at-hand, and going from one to the other is a jarring experience. But, in the weak sense, this is only temporary.
Then there's the strong sense. Some tool are just badly designed and remain awkward for the majority of users: no matter how "familiar" they may become, they remain present-at-hand. LotusNotes is a fine example, with its almost universally derided UI.