A decade ago, when she was president of product development at Genentech, she helped make that company a leader in cancer drugs–and she climbed Fortune‘s Most Powerful Women rankings to No. 13 in 2008.

A doctor who treated cancer and HIV AIDS patients in Uganda early on in her career, Desmond-Hellmann thrived on testing herself and taking career gambles that most people would only dream about. So when she left Genentech, after its acquisition by Swiss drug giant Roche in 2009, she opted to take a job as Chancellor of the University of California at San Francisco. For five years, she led a major research university with four graduate schools, two hospitals and 23,000 employees.

Last fall when Bill and Melinda Gates were hunting for a new CEO for their foundation, they quickly realized that Desmond-Hellmann wouldn’t want to be a figurehead boss. Still, Desmond-Hellmann surprised the Gates with her ardent and assured views about how she wanted to steer their $40 billion in assets.

“One of the things that came out of the interview process is that we hired a bold CEO,” Melinda Gates told me in an exclusive Fortune interview. I sat down with Gates and Desmond-Hellmann together last month in Kirkland, Washington.

The 56-year-old Desmond-Hellmann, who sits on the boards of Facebook and Procter & Gamble , admits she’s “no shrinking violet.” And Melinda Gates, whom I profiled in a 2008 cover story, confesses that she and Bill had to get their heads around their prospective hire’s boldness. “We actually had to say to ourselves as a couple, Is that going to be okay? We really are okay with this, right?,” Gates said.

Desmond-Hellmann started her job as CEO of the Gates Foundation on Thursday. In this Fortune interview, she and Melinda talk about how they met (the first time was at Sheryl Sandberg’s house, actually), how they reached a partnership deal, and how they intend to give away the Gates fortune and the many billions more that have been entrusted to the foundation by Warren Buffett .