Can a reservist or guardsman also work for a three letter US agency?

Since you brought it up..

It has been my experience that any specialty in the military which requires a security clearance probably has a 3-letter agency equivalent. For example, Spec Ops and infantry do well in any agency with a boots-on-the-ground component (although those tend to be invitation only gigs). MI has a number of agencies they can apply to. Anyone working with nuclear who takes their job seriously enough to do it well has a solid chance in DoE.

Outside of the military industrial complex, there are other agencies who are happy to employ reservists and national guard. The only exception I've seen are in work-forces who have an inherent dislike for the military (many of the congressional branch agencies and educational institutions for example).

Don't also forget that just because it's easy to jump to a government job, doesn't mean it will be a good fit. Even with the highest clearance in the most shadowy agency, the pay and benefits are easily outmatched by the private sector because the job is seen as patriotic servitude. A major example of this is in the field of software development, where a candidate with an associate's degree won't get a second nod by an agency, but can get highly compensated in private industry. Of course, this is for folks who have a great attitude and are willing to devote personal time to learning their craft. Also, the idea that a government job is forever is also not valid. I've seen tens of thousands of government employees laid off on the outsourcing whims of agency leaders.

One last thing you should consider before going into a 3-letter agency is you'll need to keep-up or maintain your security clearance. This doesn't sound like a big deal if you've had a clearance most of your adult life. But remember, your clearance is completely dependent on a random security person's evaluation of you and your lifestyle. As little as 2 years ago, I've seen very trustworthy folks lose their clearances (their ability to make money to support their family) due to allegations stemming from nasty divorces. The allegations were deemed unfounded by judges in all three cases; but, the security folks evaluating their SF-86 paperwork were pursuing their own personal moral agenda which exceeding what was required by their position, and the clearances were declined. In one case, the person who lost their clearance paid $80K over 3 years to fight the negative evaluation, and still lost. In the other two cases, they just dropped it. Now, add in the fact that for some clearances you'll need a polygraph examination every 5 years or so to determine if you are suitable for a position of trust., and you'll see why the pressure alone doesn't make it a good fit for everyone.

A regular mantra in the TS/SCI community is "if you're not doing anything wrong, you've got nothing to worry about". This has proven to be untrue time, and time again for the reasons listed above and also for things as petty as office politics where passive-aggressive evaluations of someone's work habits can also lead to the declination of a clearance.

Personally, I feel like I wasted 20 years of my life screwing around in a 3-letter agency, and when I finally broke out of the agency-cult (by choice), my life improved exponentially.

Source: After my active-duty time, my lack of a bachelor's degree made me unemployable by agencies. However, as a defense contractor I quickly (within 2 years) moved into the 6-figure range. After 13 years, I went to the private sector where my initial loss of salary was due to the inability of my new company to check my references ( a common impediment to going private-sector). However, in 2 years, I was easily exceeding my previous pay, without a degree, as a software developer. I am using to delta to pursue my bachelor's.