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I've been told by veterinarians that the best way to help animals is by donating your money and time to your local animal shelters. Most of them are very poorly funded and staffed, and this is one of the biggest reasons why so many dogs and cats are euthanized each year.
Here's a good website for finding out how much money you donate to a particular non-profit actually goes to helping the cause (instead of administration fees or marketing): CharityNavigator.org
What exactly do you mean by "mainstream groups?"