There are two core configuration scripts that control your web-server on Tomato:
lighttpd.conf (/opt/etc/lighttpd/lighttpd.conf)
php.ini (/opt/etc/php.ini)
Configuring php.ini is quite a common issue among us web-masters - just always keep in mind the real CPU/Memory capacities of your router while revising it now.
Meanwhile, lighttpd.conf might puzzle die-hard Apaches with its supreme simplicity and flexibility. Unlike Apache httpd.conf, it really looks and acts more like a script, totally based on (freely nested) conditionals with pcre support and even includes - lighttpd.conf can be split into separate include-modules (stored at /opt/etc/lighttpd/conf.d/). No .htaccess, though - conditionals control everything.
First thing you really have to check in lighttpd.conf is its "server.event-handler" value. If there's an error like "event-handler linux-sysepoll failed" in Lighty's error.log (/opt/var/log/lighttpd/error.log, by default), change it to:
server.event-handler = "poll"
Second, uncomment server.modules that you really need (and re-configure them if necessary). For starters, "mod_access", "mod_fastcgi", and "mod_accesslog" will do the job, at a minimum. Remember that (by default) your php-fastcgi module is configured via fast_cgi include-module (in conf.d/).
Third, make your decision on port assignment. Leaving Lighty on default http port 80:
server.port = 80
would definitely provide much easier setup, with one small inconvenience - you'd have to change your Tomato's webGUI port (Administration -> Admin Access), which is also listening to 80 by default.
Now, point the server.document-root to your domain, let it be:
server.document-root = "/opt/www/domains/my-domain.com/html/"
Even with simple-vhost module enabled and configured, you would still need this static document-root, for correct Lighty start-up.
Later on, for security reasons, you might wish to change server.username and server.groupname. The way you can add users and groups on TomatoUSB is described here.
And one more valuable debug tool. To validate your lighttpd.conf, fire in telnet:
lighttpd -t -f /opt/etc/lighttpd/lighttpd.conf
In return, you should get a message:
Syntax OK
Further Reading: Configuring Lighttpd