Issa's decision continues a string of GOP lawmakers who have decided to retire rather than take on what would be a difficult re-election battle.
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Democrats had made defeating Issa one of their top priorities in the midterm elections.
Issa is a longtime nemesis of the Democrats and then-President Barack Obama. He once served as chairman of the House Oversight and Government Reform Committee and led investigations of the IRS and its treatment of conservative groups and Benghazi.
The politician released the following statement:
"Two decades ago, when I stepped away from the business I'd built to enter public service, I never could have imagined that a long-shot bid for U.S. Senate would lead to 18 years in the House of Representatives and endless opportunities to make a meaningful impact.
From the first successful recall of a sitting Governor in California history, to establishing new and stronger standards for government accountability, to protecting the Internet from harmful regulation, and enacting the nation's first open data standards, we attempted and achieved much in the service of our nation.
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Together, we put an end to abusive Congressional earmarks, strengthened the Violence Against Women Act, empowered better oversight of the executive branch, and cleared the course for better intellectual property protections to stop the piracy of American ingenuity.
Throughout my service, I worked hard and never lost sight of the people our government is supposed to serve. Yet with the support of my family, I have decided that I will not seek re-election in California's 49th District.
I am forever grateful to the people of San Diego, Orange and Riverside counties for their support and affording me the honor of serving them all these years. Most humbling for me -- and for anyone who represents this area -- has been the special privilege of representing the Marines and Sailors of Camp Pendleton and their families. On countless occasions, and in every corner of the world I met them, I was inspired by their bravery and humbled by their sacrifice to keep us all safe from harm.
Representing you has been the privilege of a lifetime.
While my service to California's 49th District will be coming to an end, I will continue advocating on behalf of the causes that are most important to me, advancing public policy where I believe I can make a true and lasting difference, and continuing the fight to make our incredible nation an even better place to call home."
The Associated Press contributed to this report.