In early October 2004 Reeve was busy promoting The Brooke Ellison Story, which he had directed, and Dana Reeve was appearing onstage in Los Angeles in Brooklyn Boy preparing to bringing the play to New York. It was the first time she had been away from her husband and son for an extended period. At the time, Reeve was being treated for a pressure wound, a common complication for people with paralysis that he had experienced many times before. The wound had become severely infected, resulting in a systemic infection; yet there seemed no unusual cause for concern. On Saturday, October 9th, Reeve attended one of Will's hockey games. That night, he went into cardiac arrest after receiving an antibiotic. He fell into a coma and was rushed to Northern Westchester Hospital. Dana Reeve would later point out that Reeve had a history of being sensitive to drugs that were usually well tolerated by most people. With the help of Robin Williams' wife, Dana was able to board a plane and rush cross country to join Alexandra and Will at her husband's bedside; arriving shortly before his death on October 10. Christopher Reeve was 52 years old.
On November 3, 2004, the board of directors of the Christopher Reeve Paralysis Foundation unanimously elected Dana Reeve as their new chairperson and she dedicated herself to carrying on her husband's work. Dana had been used to being in the background of her husband's very public efforts, but as she said in May 2005: "Suddenly, I feel like I don't have that choice anymore. I have to carry on his mission." Dana insisted on going over every grant proposal, lobbied and endorsed politicians, was writing a second book, and made national television appearances both solo and with her son, Will, four months after Chris's death and in the immediate time following her own mother's death. She made plans to resume her singing career. But in an unbelievably cruel twist of fate, less than a year after Christopher Reeve's death, his beloved wife was diagnosed with lung cancer. "What I didn't know is that lung cancer is the number one cancer," said Dana to Kathie Lee Gifford. "I was always looking for breast, ovarian and uterine, and you think, I'm a non-smoker and I live in the country, so I'm good. So I am completely shocked." She also talked about having a cough that lasted for weeks leading her to get diagnosed: "I did, and people were saying, 'Oh allergies, allergies,'.. The doctor wasn't even going to take a chest X-ray. He was like, 'you're healthy'.. and then it was huge. I probably had it for about a year." She fought the disease with grace, courage, and the humor that had characterized both her and her husband as she endured rigorous bouts of chemotherapy. Wearing a wig after her hair fell out, Dana appeared upbeat as she attended the annual Reeve Foundation fundraiser in November 2005 and sang "Now and Forever" in honor of their friend, Mark Messier, a retiring New York Ranger, at Madison Square Garden in January 2006. Sadly, at the age of 44, Dana lost her battle with cancer on March 6, 2006. She had made arrangements with family and friends for the care and future of their 13-year-old son. Alexandra, Will, and Matthew arrived arm in arm to speak at a private memorial service for Dana, as they had done less than 18 months earlier for their father.
Christopher Reeve left a body of artistic work that continues to inspire and entertain millions of people. He also left a left a legacy that includes love of family, heightened awareness and funding to help people dealing with disabilities, and therapy breakthroughs brought about by greater funding for spinal injury research. Donations to the Christopher Reeve Foundation have only increased since the Reeves' deaths; and in July 2006, Christopher's adult children, Matthew and Alexandra, were added to its expanded board of directors. But perhaps most significant is the inspirational example described by Reeve's mother, Barbara Johnson, in 2006: "I think one of the most important things that Chris did for many, many people was, after his accident and becoming a quadriplegic, he showed them that there is life after a spinal cord injury or after a stroke. You don't have to sit in the dark feeling sorry for yourself. I think that he touched many, many, many people and certainly that was an enormous contribution to the quality of life of the people who had been afflicted with something as restrictive or disabling as a spinal cord injury. He didn't just help quadriplegics like himself," added Johnson. "I know for a fact that a lot of others were kind of led to thinking their way into a happier, more productive life. And that may well be his most lasting contribution."