A few links here to causes I support, and brief notes on why. I'm leaving out the more political organizations, though some of these do lobby politicians on behalf of their causes to some extent.
PROTECT: The National Association to Protect Children actively lobbies government officials for more resources to help children at risk and victims of child abuse (be it emotional, sexual or otherwise) and for tougher penalties against those who harm children. Pro-child, anti-crime. It SHOULD be the default position. Donations to PROTECT aren't tax-deductible because it conducts direct lobbying; there's also a related educational group called Promise to Protect, where donations ARE tax-deductible.
Sweet Relief Musicians Fund: Musicians and other artists don't have an easy life, as a general rule. Most who try to make a living with their art don't. Health insurance, in particular, is out of the reach of many Americans, especially self-employed persons -- which includes most artists. This cries for change, change at a government level in my opinion, but in the meantime, here's an organization that helps musicians and music lovers join together to help musicians who face serious illness and big medical bills.
The Hero Initiative/formerly ACTOR (A Commitment To Our Roots): See above description of Sweet Relief but change the term "musicians" to read "comic book creators," and the overall message applies here.
Kristin Brooks Hope Center/Hopeline: This organization runs the toll-free suicide prevention hotline 1-800-SUICIDE. I've fought my own battle with depression for years, and I know others who have lost the battle, one of them the young lady who was the first person for whom I ever shelled out corsage money.
Kiva: Microfinancing is an innovative way of giving a hand up, not just a handout, to entrepreneurs in developing nations and your own backyard. There are a few groups that do this -- and the founder of one of the first micro-lenders, the Grameen Foundation, rightly won a Nobel Peace Prize for his idea.
Unitarian Universalist Service Committee: Some religious charities demand recipients of their aid listen to a sermon or make (or fake) a religious conversion. Some waste money meant for food and water on religious tracts instead. The UUSC doesn't do that. Nor, to my knowledge, do the American Friends Service Committee (the Quakers) or Episcopal Relief and Development.
Christopher and Dana Reeve Foundation: The real-life Man of Steel didn't surface until after his onscreen adventures as Superman had ended. The foundation named for the late actor and his late wife continues its work raising money for paralysis research and increasing awareness of people with spinal cord injuries.