Another major shift in runes came with D2R Ladder Items. Blizzard decided to replace Horadric Cube with a much more restricted version, Kanai Cube. This meant that runes wouldn't play as significant a role in crafting, although a few Kanai Cube recipes require an item called Khanduran Rune. This item isn't part of the skill rune system developed for the game, though. The change would also mean that sockets would now only be used to hold gems and jewels, not runes. Gems would later on become Diablo's most controversial monetization policy.

Initially, the runes in Diablo 3 were items, not unlike those from Diablo 2. They also took the color aspect from the first Diablo runes and were described according to their colors, Crimson, Indigo, and so on. However, eventually during development Blizzard would switch them to non-item skill enhancements, which Diablo 3 launched with.

Each iteration of runes has had differing hieroglyphs, and there hasn't been a clear pattern. The latest runes in Diablo 3 come the closest to describing the effects of the runes, but still, leave a lot of room for interpretation. The Overpenetration has a line double strikethrough, Grievous Wounds has an area with jagged edges, and Chemical Burn has what looks like a flame. However, those same five hieroglyphs are used for various effects that are not consistent with the imagery.

Examples of Diablo 4 runes. Effect Runes and Condition Runes. Not final versions.

In Diablo Immortal, runes took yet again a new form. A total of 15 runes exist, and they are divided into Common Runes and Uncommon Runes. These runes serve as a requirement for crafting Legendary Gems in Diablo Immortal unless players want to pay for them with real money. While the rune system isn't as robust as in previous Diablo titles, using runes is vital to accessing the best equipment. Though the runes look similar to buy d2 resurrected items, the hieroglyphs, and names have been altered.

Blizzard is undoubtedly going to bring runes to Diablo 4, too, and make them a more integral part of the game. Runes are going to be pocketable again, and powerful runewords from Diablo 2 are making a return. The hieroglyphs will be inspired by Diablo 2, according to Blizzard's development updates. One new addition to the rune mechanic is that the runes will be divided into two categories: Condition Runes and Effect Runes. Condition Runes set a condition under which the socketed equipment gains a bonus. Effect Runs determine what type of boost or ability the equipment is going to get.

Blizzard has also revealed that there will be rune progression, like in Diablo 2. This might allow combining more than two runes as well as recycling them for more powerful ones. It might also mean that Horadric Cube, or some iteration of it, could make a comeback. Unfortunately, most of the information on Diablo 4 runes is from a couple of years ago, so there's no clear idea how much the mechanics, or the hieroglyph visuals, have changed. Perhaps one of the upcoming Diablo 4 Quarterly Updates will touch on runes, runewords, and hieroglyphs.