The main issue with Guile is the same issue as with any other Scheme, and that issue is that it is a Scheme. No single Scheme is widely adopted and the main reason for that is extreme balkanization. You dont write code in Scheme, you write Guile, Racket, Chicken, etc.
The Scheme philosophy, which was developed in opposition to batteries-included aka "bloated" Common Lisp, was to have a small core and emphasize simplicity, purity, etc. For years proponents of Scheme have emphasized how beautiful and simple the small standard of 50 pages is, compared with Common Lisps "bloated" 1000+ pages standard.
This had two consequences:
1. It was extremely easy to write a scheme implementation, soinstead of writing code _in_ scheme, people wrote _schemes_. Hundreds of them. And while other people spent the last 20 years writing thousands of useful libraries in C, python, java, scheme implementors spent reinventing the wheel, over and over and over and over again. Today there are more implementations of scheme than libraries in scheme.
2. The emphasis on "small core" might be cute for teaching SICP, but in order to be able to do anything useful with the implementation, it forced the implementors to reinvent the wheels for everything else. And each implementation did it their own way because standardization was considered "selling out" and aping the nemesis Common Lisp. This led to _extreme_ code unportability.
Nowadays they are somehow trying to standardize, but with the consequence that they are realizing that by doing that, they are becoming indistinguishable from their old nemesis Common Lisp, which went through the same balkanization phase 20 years ago, so the point of splitting off Scheme from Lisp is becoming questionable. Instead of wasting precious time writing 1001 scheme implementations, they could have spent the last 20 years writing useful common lisp libraries and competing with other batteries-included languages like java and python.
In short: Besides the social problems that every Scheme suffers from and the Lisp world suffered during the 80s, Guile on its own is doing quite well. Once it is integrated into Emacs, Emacs will become Guile's killer app, boost its popularity and set it apart from other schemes.