[3] The hospital is affiliated with the University of Pittsburgh School of Medicine and features a state-verified level 1 pediatric trauma center, one of four in the state.

After a small fire at the mansion, fundraising began for a much larger facility which was begun in 1926 at the DeSoto Street location in the Oakland section of Pittsburgh.

In 1947, doctor Jonas Salk took a job at Children's and at the University of Pittsburgh School of Medicine as an associate professor of bacteriology and the head of the Virus Research Lab.

Salk went on CBS radio to report a successful test on a small group of adults and children on March 26, 1953, and two days later, the results were published in The Journal of the American Medical Association.

[22] In 1981 pioneering surgeon and "Father of Transplantation" Dr. Thomas E. Starzl came to the hospital, on condition that he would be free of administrative tasks and able to focus on medicine.

Byers W. Shaw Jr. and Henry T. Bahnson successfully completed the world's' first simultaneous heart and liver organ transplant on six-year-old Stormie Jones at the Children's Hospital of Pittsburgh.

[28] Starzl was the head of transplantation at the hospital until 1991 when he stepped down from clinical and surgical duties and shifted all of his focus to research.

[31] The new tower also included an underground parking garage, new lobby, pediatric and neonatal intensive care units, operating rooms, and a radiology department shared with the neighboring Presbyterian Hospital.

[39][40] A few months later insurance company Highmark filed suit to block Children's planned merger with UPMC, claiming that UPMC could use the region's only pediatric hospital as part of a plan to build its own insurance business by blocking access to CHP for patients with other coverage.

[46] On December 18, 2009, UPMC announced plans to demolish a large section of the former Children's Hospital, including the building on the corner of Fifth Avenue and DeSoto Street.

[49] Ideas were floating around as early as 2000 when CHP conducted a study to determine the cost of renovating the original hospital on Fifth Avenue and DeSoto Street in Oakland, contracting RossBianco Architect to create a master plan.

They determined it would cost about $185 million to upgrade electrical systems and rooms, but wouldn't address problems with the outdated hospital design itself.

A few sites were considered including a lot next to UPMC Magee-Women's Hospital, which was ultimately not chosen due to the lack of expansion potential.

A lot at LTV Steel site along the Monongahela River was also considered and turned down due to the potential cost of environmental cleanup that option entailed.

[53] As plans were being drawn up, leaders from the St. Francis Medical Center in Lawrenceville announced that they would be closing due to long-term financial struggles and were looking for a buyer.

[54] After financial donations from Highmark, UPMC officials decided to purchase the St. Francis Medical Center, providing large amounts of land and expansion potential.

In addition, rooms at the new hospital are completely private featuring an overnight couch with pull out bed for caregivers.

[69] Along with the physical upgrades, CHP implemented an advanced new electronic health record system (EHR) as a part of the new hospital.

[83][84] In the wake of the 2020 Coronavirus Pandemic the hospital revised its visitor policy to only allow two parents of each child on the inpatient wards.

[88][89] The unit is named "UPMC Children’s Harrisburg" and features telemedicine connections to the main hospital in Pittsburgh.

[100] As part of the research center, Children's Hospital regularly conducts clinical trials to solve many of today's pediatric health challenges, including cancer, diabetes, heart disease, and liver and intestine transplantation.

[109][110] UPMC Children's Hospital of Pittsburgh is connected to the Ronald McDonald House via a third floor enclosed walkway, effectively within the same building.

[113] The same year, CHP was recognized for leading the way in advanced technology as the first and today's only pediatric hospital in the United States to achieve Stage 7 recognition from HIMSS Analytics for the use and implementation of electronic medical records.

[115][116] In 2015 CHP was named HIMSS Enterprise Davies Award recipient due to its advanced EHR system in place.

[117] In 2020 the hospital was recognized by Human Rights Campaign Foundation as a "Top Performer" in their forward thinking LGBTQ policies and initiatives.

[118][119] As of 2023 the hospital was ranked as number eight on the best children's honor roll in the United States by U.S. News & World Report.

As of 2022, UPMC Children's Hospital of Pittsburgh has placed nationally in all 10 ranked pediatric specialties on U.S. News & World [124]