Difference between = and Ctrl + =

= can only be entered at the beginning of a cell and then interprets the entire cell content as a free-form WolframAlpha query. By contrast, CTRL-= can be used to create an inline WolframAlpha interpretation cell that appears in the middle of an otherwise normal expression.

For example, we can start by typing ImageDimensions[ followed by CTRL-= to create an inline cell:

We then enter our query text...

... and then press ENTER:

Finally, we can type ] to close the expression and then evaluate it:

If we click the checkbox within the inline cell then that cell will be replaced with the equivalent Mathematica expression.

To add to WReach's answer, since = works on the entire cell, it can return formatted Wolfram|Alpha pods when there is no corresponding Wolfram Language syntax. It wouldn't make much sense to have a formatted W|A pod inline.

Compare =

vs CTRL-=

Clicking on the gray question mark says exactly this: