I've put together some custom CSS that simplifies the look of the site, tightens up some margins, reduces text size, and saves some vertical space.

Updated for the redesign. Here's a screenshot of what it looks like: https://i.imgur.com/EuZrJZw.png

Just paste into the custom CSS section of the advanced user settings page, or use a browser plugin like Stylus

body {
    font-size: 80%;
}

div#page {
    margin: 0;
    padding: .25rem .5rem;
}

header {
    margin:0;
}

header#top h1 {
        position: absolute;
        font-size: 1.2em;
        margin: 0 1.35em;
}

header#top menu {
    margin-top: 0px;
    padding: 2px 1rem;
}

header#top menu.main {
    font-size: 106%;
    margin-left: 4em
}

.tag-list-header {
    font-size: .9em !important;
    margin-left: .1em;
    margin-top: .1em;
}

#tag-list > ul {
    margin-bottom: 0;
}

div#page aside#sidebar h1 {
    font-size: 1em;
}

.search-help {
    font-size: 0.8em;
}

#nav-links {
    border: none !important;
    padding: 4px !important;
    border-radius: initial;
}

#add-fav-button {
    box-shadow: none;
}

#remove-fav-button {
    box-shadow: none;
}

.bottom-notices > div {
    border: none;
}

#artist-commentary {
    border: none !important;
    box-shadow: none;
}

#comments {
    padding: .01em 1rem;
    box-shadow: none;
}

#search-box #tags {
    border-radius: 2px 0px 0px 2px;
    box-shadow: none;
}

#search-box button {
    box-shadow: none;
    padding: 1px 5px !important;
    border-radius: 0px 2px 2px 0px;
    background: #e7e7e7 !important
}

.wiki-link {
    margin-right: 0 !important;
}

.search-inc-tag {
   margin: 0px -1px;
}

.search-exl-tag {
    margin-right: 1px;
}

Optional smaller fav button:

.fav-buttons {
    font-size: 1em !important;
    margin-right: .7em !important;
}

Remove tag type headers:

.tag-list-header {
    display: none;
}

I've also made a quick Firefox Color theme to go with it: https://color.firefox.com/?theme=XQAAAAIUAQAAAAAAAABBqYhm849SCia2CaaEGccwS-xNKlhLliJ51ygIDSHb1doLaygW8Bddi9GoqshZlsLqwbpbODZCBui7Qg-sAra5UM5Vbf4flMlTTRMY4frhLzqzYV1JPal1SK8-J1jzGNCKwK9fKK8PtQ-8oNk2YxeRwQReQS7rvey4HClAHnV6R4GuuG0A4JvkCr522syakes_QSJKTceLDN7GOVuT3mf2YPWWQavRZnTOjE5RPhJ95xd2I0hVfN2H_-LaJAA

There is a code block you can use, eg:
\

\

Chaser said:
There is a code block you can use, eg:
\

\

Thanks, I didn't see that option. I've edited my post.

I'd highly recommend using a normal firefox theme as opposed to Firefox Color, because Firefox Color increases startup time by way more than it logically should.

I took things a little further and wrote out a lot of the box-shadows. Also converted it to a UserCSS file.

/* ==UserStyle==
@name           e621-Flat
@namespace      https://e621.net/forum/show/275884 with edits
@version        1.0.0
@description    Makes e621.net flat and saves some space
@author         Syne Ardwin / RlctntFr
==/UserStyle== */
@-moz-document domain("e621.net") {
    body {
        background-image: none;
        background-color: #152f56;
    }
    #header {
        margin: 0 0 0 0;
        background-color: #031131;
    }
    #subnav {
        margin: 0 0 0 0;
        padding: 2px 20px 0px 15px;
        box-shadow: none;
        border-radius: 0px;
    }
    #ad-leaderboard {
        background: none;
        box-shadow: none;
        top: 0px;
        padding: 0px;
        margin-bottom: 12px;
        left: 3px;
    }
    #ad-leaderboard-content img {
        border-radius: 4px;
        box-shadow: none;
    }
    #content {
        margin: 0 0 0 0;
        box-shadow: none;
        padding: 10px 10px 10px 17px;
        border-radius: 0px;
    }
    .status-notice {
        top: 0px;
    }
    #notices {
        background-color: #152f56;
        padding: 0px;
    }
    #notices > * {
        margin: 5px 10px 0px;
    }

    span.thumb a {
        box-shadow: none;
    }

    input,
    textarea,
    select {
        box-shadow: none;
    }

    #paginator a {
        box-shadow: none;
    }

    .response-list > .comment,
    blockquote,
    .section {
        border-top: none !important;
        box-shadow: none !important;
    }

    .rounded {
        box-shadow: none;
    }
}

Reposition Favorite button, make it vote up automatically.

// ==UserScript==
// @name        ESFav++
// @include     https://e621.net/post/show/*
// @include     https://e926.net/post/show/*
// ==/UserScript==
var li = document.getElementById("add-to-favs");
if (li)
{
  li.style.position = "fixed";
  li.style.right = "0";
  li.style.bottom = "50%";
  li.style.width = "auto";
  li.style.fontSize = "28pt";
  li.style.opacity = "0.8";
  var li = li.children[0];
  if (document.getElementById("voteup").className != "greentext")
  {
     li.setAttribute("onclick",li.getAttribute("onclick").replace("return false;",document.getElementById("voteup").getAttribute("onclick")));
  }
}

I've overhauled this for the new site. Same concept but for the new theme.