Brendan Drumm, Professor of Paediatrics at University College Dublin and Our Lady's Children's Hospital, was appointed as its first CEO.

In 2005 the HSE commissioned McKinsey & Company to undertake a review of the strategic organisation of tertiary paediatric services for Ireland that would be in the best interests of children.

It recommended that, in view of Ireland's size and expected demand, there should be a single tertiary paediatric hospital based in Dublin, with good transport and access links, room for future expansion, ideally co-located with a leading tertiary adult centre, and "at the nexus of an integrated paediatric service" with urgent care centres around Dublin and with regional children's hospitals around the country.

McKinsey was not asked to identify a site but proposed nine assessment criteria for making a decision on the best location and model.

[5] It was also quickly accepted by Government and it agreed to proceed with the single tertiary hospital model with satellite urgent care centres.

[1] The chairman of the board, Philip Lynch, resigned unexpectedly in October 2010 citing "significant and fundamental differences" with Harney over the chosen location of the hospital, as well as over funding arrangements and governance.

[17] Harney announced that she had requested Lynch's resignation, stating that "it is not in the remit of the Development Board to revisit the Government decision taken on the location of the new hospital".

[16] Lynch was replaced as chairman of the NPHDB by the businessman John Gallagher, who himself resigned only months later in March 2011, saying that he "no longer feels that he has the mandate to continue with his original remit to build the hospital at the Mater site", since the new Minister for Health, James Reilly, had publicly considered reviewing the decision to locate the new hospital there.

In February 2012, An Bord Pleanála announced that it had refused permission for the project, stating in its decision that "by reason of its height, scale, form and mass, located on this elevated site, [the hospital] would result in a dominant, visually incongruous structure and would have a profound negative impact on the appearance and visual amenity of the city skyline," as well as constituting over development of the Mater campus and detracting from the historic character of the surrounding area.

[20] In the wake of the refusal of planning permission, Reilly tasked another review group (led by the businessman Frank Dolphin) to determine other options for the new hospital.

[21] The group also received, but chose to exclude, a number of unsolicited site offers that were not linked to a Dublin teaching hospital.

[39] The government confirmed in February 2024 that the total sanctioned budget had now reached €2.24 billion, and that this would now be the "maximum allocation", with no further funding to be put towards the project.

The plans include 380 individual inpatient rooms, about the same number as Great Ormond Street Hospital, each with en-suite facilities and a bed for a parent or carer to sleep on.