Depends on what you're talking about, but typically, yes.
Content is released as one of 3 things;
- Permanent. It will always be available in the store not matter what.
- Legacy. It will be in the store for a certain period of time (like during a Holiday event) then it will go into the 'vault'.
- Limited. It is only available for a short period and will probably never return.
Legacy skins can be obtained through Hextech Crafting and Mystery Gifts, and frequently return to the store during later events (usually the same event it was released in) or in Bundles.
Limited skins have a near zero chance of ever being obtained again, and cannot be acquired through Hextech Crafting or Mystery Gifts.
You can find the list of Limited and Legacy skins here; https://support.riotgames.com/hc/en-us/articles/201752944-Guide-to-Legacy-and-Limited-Skins
You can find out how the content will be available on the front page when something new is released. Is there a specific item you're wondering about?