High-profile cases include the successful defense of U.S. President Clinton's impeachment, representation of Enron's law firm Vinson & Elkins, representation of the motion picture studios in the Kazaa/Grokster file-trading litigation, defense of the Vioxx cases, and counsel for the plaintiff states in the United States v. Microsoft antitrust remedy trial.

The firm represented Lieutenant Colonel Oliver North during the Iran-Contra Affair and John Hinckley, the would-be assassin of Ronald Reagan.

[2][3][4] Williams & Connolly partner Robert Barnett has represented Barack Obama, Bill Clinton, George W. Bush, James Patterson, Hillary Rodham Clinton, Michelle Obama, Laura Bush, Bob Woodward, Sarah Palin, Dick Cheney, Alan Greenspan, Katharine Graham, Ben Bernanke, Paul Ryan, Tim Russert, Barbra Streisand, Jack Welch, Khaled Hosseini, Bill Walton, Mitch McConnell, Jake Tapper, and others.

The firm's corporate clients include Google, Disney, Samsung, Intel, Bank of America, The Carlyle Group, Medtronic, Genentech, Eli Lilly, Halkbank, and 21st Century Fox.

[10] Prominent alumni of the firm include: Over the past decade, 45 Supreme Court clerks have been full-time or summer associates with Williams & Connolly.