All security becomes a trade-off. The more secure your machine is, the more inconvenient some things become. Applying extremely strict rules with Lokkit will mean that you need to learn new ways to do some things. The most commonly-used applications which are affected are listed here:
FTP has two modes of operation, one of which is firewall-friendly. Modern FTP clients tend to support the friendly mode (really called passive mode).
Netscape automatically uses passive mode for FTP.
The command-line ftp client will use passive mode if run as pftp not ftp.
The ncftp client will use it when run as ncftp followed by set passive yes at the prompt. (The ncftpget command for getting just one file can be started in passive mode as ncftpget -F)
The GNOME ftp client, gftp, will use passive mode. Start it via Programs->Internet->gFTP. Passive mode will probably be enabled by default, but you can check by selecting FTP->Options. There will be a checkbox for Passive file transfers. You want this to be checked.
Realaudio and RealPlayer default to using UDP which is hard to firewall. For RealPlayer, you can change it to TCP, which passes firewalls, by following the directions at real.com's Knowledge Base. Essentially, you want to change all mentions of "stream type" from "UDP" to "TCP" in the Preferences dialogue box.
When using IRC clients, you will be unable to make DCC connections. There is no way around this.
Networked Quake will also be affected. There are workarounds for this but they are complicated. The author does not play Quake so would appreciate suggestions on this which are simpler than the Linux IP-Masq-HOWTO document.