Lord knows I'm no expert on this kind of thing, but I've done a lot of epub -> mobi conversions (without having an actual kindle to test them on). Also, mostly I do fiction, so I'm usually not concerned with footnotes, illustrations, etc. My epubs are produced initially from the InDesign print book files, and heavily tweaked in sigil, by the way. Here are my observations:
Mobi format uses a table of contents (TOC) that is an "inline" html file, whereas epub uses the toc.ncx file for the same purpose. Typically, epubs do not also have an "inline" TOC within the book itself.
Given a valid epub, suitable for publication at, say, Apple Ibooks, conversion via kindlegen will not produce a TOC in the mobi. Calibre WILL produce the TOC, but it will be placed at the end of the mobi. Not an issue in a practical sense, since there will be a guide element that allows one to jump to the TOC from wherever you are, wherever the TOC is actually located. Nevertheless, the preferred place for the TOC is between the frontmatter and the "start reading" point of the book (i.e. Chapter One, or the Preface, or whatever).
However, as noted above, there is seemingly a problem with Calibre-produced mobi files not being quite compatible with Kindle DRM. In my case, my publisher prefers NOT to use DRM so we have not had any problems with this so far.
There is another issue, regarding the cover image. Given a valid sigli-produced epub, kindlegen will produce a mobi that has TWO cover images. That is, the cover image will be displayed, and on the next page, the cover image will be displayed again. This is IMHO a cosmetic issue that would likely not be noticed by the average reader, unless they navigate to the cover and then page through the ebook one page at a time, to see the frontmatter, rather than just starting at the first chapter.
And then there's the "start reading" thing. In the epub you're starting with, you can flag a given file (typically a chapter) with the guide element 'type="text" '. If the title of that element is "start reading", then the mobi file will open to that page. In order to achieve this you will have to expand the epub, edit the content.opf file, and re-zip the epub. Calibre will not respect this, however. But kindlegen will. So there's a point in favor of kindlegen.
That said, there have been a few instances where kindlegen did not properly render certain <span> elements in the mobi output, whereas calibre got it right.
So there are no absolutes, no guarantees.
If you're looking to convert epubs to mobi for your own private use, then it's a no-brainer to just use calibre. They'll work fine.
But if you want to create "PROFESSIONAL" mobi's from good epubs, then you've got some work ahead of you.
To answer the OP's original question, if I want to create a professional quality mobi, I will expand the epub and edit the content.opf file to suit, and then use kindlegen, with all its warts, to do the conversion. Then I will thoroughly check the output mobi, in all the mobi readers I can muster, to see if it all worked out as I expected. Lots, of work, but that's why they pay me the "big bucks" -- NOT!
BTW, as I said, I am no expert. If you want a real opinion, check with Hitch.