Well. I used to bemoan the big chains when I ran a shop in a small chain!
Now I refer customers to whichever shop I think is most likely to have what a customer wants, and I know I get referrals from staff (and head of dept./lower management) at most of the bigger bookshops here...

The main gripe I used to have was that in recent years the big chains secured a real grip on PR and author tours that small shops just can't break into. In the past I put on signings by some pretty big names but even before I started Transreal Fiction that had pretty much dried up, even though I worked for a specialist sf/comic chain with a good customer base. Now, as a small independent shop, I sometimes have authors drop in and sign stock but I've never held an actual 'event'. I'm just too small to compete with dedicated PR departments to try to get signings.

The other issue is book pricing. The UK used to have a Net Book Agreement which meant that you had to charge the publisher's stated price. No discounting.
Now you can sell books at whatever price you like, which is fine - usually we all still charge the cover price! The most annoying exception is the big-name hardback release. Bulk buying by the chains can enable them to negociate deeper discounts and slap a sticker on saying '3.00 Off' or 4 or 5 or, sometimes even 6 - i.e. almost 10 dollars off a 25 - 30 dollar book. Sometimes I'm paying as much as they're selling it for!
Usually I have an idea which books might get this treatment - and I don't bother getting them! Or I might get one copy of the latest Stephen King book, or, alternatively, be stuck with a pile of David Eddings because I didn't know a chain had got a good deal and were able to knock 5.00 off the price. But I can usually guess which authors it might happen with and I have pretty good supply lines, so I never have huge amounts of anything in stock...
(I mostly use a big wholesaler for UK stuff and order twice a week, with next day delivery and also a big US wholesaler whom I order from weekly and usually get the order through before the next one is placed. So I don't need to pile up stock. It's v.rare for me to have even ten of anything in stock - except the hottest new paperbacks...)

And I don't actually have any Varley on the stock shelves!
Just his latest hardback, Red Thunder, which is an enjoyabe, light read. Like a Heinlein juvenile, or a good Tom Swift book! :b
A bunch of college kids build a spaceship; good thing they happen to fall in with a crazy inventor who has just harnessed zero point energy, or something! Lets go save the manned mission to Mars which has just exploded en route!
(Yes, I do research my stock quite thoroughly sometimes!)

(and, finally, the big chains themselves moan about the supermarket chains doing the same thing to them! Given the right titles, they can discount even deeper than the booksellers!)

Long answer; hope it's useful - feel free to ask more.