The leadership vacancy created by Homeland Security Secretary Janet Napolitano’s resignation is the latest blow to a department where one-third of the heads of key agencies and divisions have been filled with acting officials or remained vacant for months.

Napolitano’s departure, slated for September, will create the 15th hole in the department’s 45 leadership positions. Napolitano’s chief of staff and the director of Immigration and Customs Enforcement are leaving this month.

The deputy secretary, general counsel, heads of Customs and Border Protection, privacy, legislative affairs, intelligence and analysis and more are filled with acting officials. Other key positions, such as the executive secretariat, inspector general and deputy undersecretary for cybersecurity, remain vacant.

The pattern of putting acting officials in leadership positions at the Homeland Security Department— sometimes replacing acting officials with other acting officials — has been going on for months. This swath of vacancies raises questions about how a department depleted of permanent leadership could implement changes, particularly as Congress considers overhauling the nation’s immigration system.

“Her departure is a substantial addition to the growing list of unfilled key leadership positions within the department,” Rep. Michael McCaul, R-Texas, who chairs the House Homeland Security Committee, said of Napolitano’s resignation. “The administration should move swiftly to fill the gaping holes in its management.”

The White House referred a request for comment to the Homeland Security Department, which did not respond.

The Homeland Security Department is composed of agencies that protect the president, respond to disasters, enforce immigration laws and secure air travel. Many of the unfilled leadership positions don’t require Senate confirmation.

Napolitano on Friday announced she would be leaving her post in early September to become the president of the University of California school systems. It was not immediately clear who the president wants to replace her.

The acting deputy secretary at the department is poised to take over as acting secretary unless the Senate confirms the president’s nominee for Homeland Security deputy secretary before Napolitano leaves. If that happens, the new deputy secretary would assume the role of acting secretary until the president names a replacement.

While some of these vacancies have little impact on daily operations around the country, the lack of permanent leadership at the top can have long-term effects over policy, said Richard Skinner, the department’s former inspector general. There has been no permanent replacement for Skinner since he left two years ago.

Acting officials are always reluctant to make long-term policy calls, said James Ziglar, the last commissioner of the Immigration and Naturalization Service, which was absorbed into the Homeland Security Department in 2003.

“On the administration side, management side, everyone is looking at the person, saying, ‘You aren’t going to be around very long, so we’re going to just hold off doing stuff,’ ” Ziglar said.

Customs and Border Protection, which oversees the securing of the nation’s borders, has not had a Senate-confirmed leader since the George W. Bush administration. President Barack Obama in 2010 exercised his ability to bypass Congress and appoint Alan Bersin as head of CBP. But that appointment was up at the end of 2011. The acting commissioner who replaced Bersin recently retired from government, only to be replaced by another acting commissioner.

Without a Senate-confirmed commissioner of CBP, it will be difficult to put in place and actual border strategy, said Ali Noorani, executive director of the National Immigration Forum.

The Democratic-controlled Senate has passed an ambitious and broad immigration bill, which includes doubling the size of the Border Patrol to more than 40,000 agents, offering a path to citizenship for immigrants in the country illegally and increasing the number of people who come to the United States as temporary workers. House Republicans have vowed to fight the bill, arguing that the border isn’t secure and that must come first.

“Whoever is in the position is always looking over their shoulder, wondering if they are going to have a job,” Noorani said.