For the first time, I am going to make a site to support Spanish and English (default). So far, I have two resource files: MyResources.resx and MyResources.es.resx. I am using the neutral culture without any problems.

With all your experience, does anyone see a concern with this approach? May I overlooking something really important?

Thanks for sharing your experience on this item.
 

There shouldn't be any problems with this.  If anything it's the right way to do it. Consider this: if you were to only use a non-neutral culture (e.g. es-MX) then any person from another Spanish locale would get the default resource values.  Since you have the es culture though, it will apply to anybody using an es-* locale.

 Thank you for confirming this approach! My manager and I appreciate it