Well, I’m not an expert - but as the default Casper theme already uses flex, and is responsive, clearly it is possible.
As to the CSS - if you have an example of something you like, you could just investigate how they do it, and replicate it. For example on the URL you identified, it looks like the large images are a single post in a big div, followed by another div of exactly same size - but the second div contains two half-sized divs i.e.