Rancic joined E! network’s E! News as a reporter in 2002 and became an anchor in 2005. Over the years, she has shared co-hosting responsibilities with Ryan Seacrest, Terrence J, and Jason Kennedy.

On December 15, 2006, Giuliana and Bill Rancic announced their engagement. They were married on September 1, 2007, in a ceremony on Capri at Sancta Sophia Church in Anacapri.

Additionally, she co-hosts E!’s Fashion Police and often co-hosts red carpet events for award shows, such as the Golden Globes and the Academy Awards. She is the creator and executive producer of MTV’s Celebrity Rap Superstar, which premiered in 2007. She and her husband, Bill Rancic, star in the reality-television show Giuliana and Bill which aired on E!. She appeared in the movie Bring It On: Fight to the Finish in a brief scene. Rancic also has hosted the Miss USA and Miss Universe beauty pageants on NBC.

The two have publicly discussed their fertility issues on television talk shows, having tried to conceive since approximately the beginning of 2009. The couple began in vitro fertilization (IVF) in March 2010, and Rancic got pregnant in the spring of 2010, but she miscarried at nine weeks. She had an IVF transfer for a second time in November 2010; however, the procedure did not result in a pregnancy. When the couple decided to try for a third round of IVF, her doctor recommended a mammogram, which is how she found out she had breast cancer. Despite her condition, the couple were still motivated to have a baby, so they continued with the egg retrieval and found a surrogate.

In August 2011, Rancic and her husband announced plans to open a restaurant in partnership with Lettuce Entertain You Enterprises. The restaurant was named RPM Italian, with a menu including dishes inspired by Rancic’s mother, “Mama DePandi”, and it opened in the River North district of Chicago in February 2012. The partnership opened several more restaurants, including RPM Steak in Chicago, another RPM Italian in Washington, D.C., and a planned RPM On the Water opening in 2019 in Chicago. The restaurants have been popular with celebrities, including President Barack Obama and First Lady Michelle Obama.

On October 17, 2011, during an interview on Today, Rancic announced she had been diagnosed with early stage breast cancer, for which she would be treated with a double lumpectomy, followed by radiation. She underwent surgery in mid-October 2011 and returned to work at E! News about a week later. On December 5, 2011, Rancic disclosed she had decided to undergo a bilateral mastectomy.

On April 23, 2012, Giuliana and Bill announced on The Today Show that they were expecting their first child via a gestational surrogate. Their son was born in late August 2012.

In 2013, Giuliana launched her clothing line, G by Giuliana, on HSN. She also launched a wine line, Xo, G.

In 2013, Rancic, who has a history of breast cancer, founded Fab-U-Wish, a charity that grants wishes to women undergoing breast cancer treatment.

Rancic was ranked #93 on the Maxim Hot 100 Women of 2004. She was also featured in People magazine’s 100 Most Beautiful of 2006 issue. Giuliana was nominated Favorite TV Celebreality Star for the 2012 People’s Choice Awards. In June 2014, Rancic was named “Fan Favorite” during the Daytime Emmy Awards. She dedicated the award to her six million followers on social media.

In February 2015, Rancic faced backlash over her controversial comments about synthetic dreadlocks worn by Zendaya at the Oscars, remarking that the hair looked like it smelled of “patchouli and weed”.

On July 10, 2015, Rancic announced that after nearly a decade, she would be leaving her position as co-anchor on E! News, yet would continue to be the host of Fashion Police. On September 4, 2018, the personality returned to the role of anchor.