Here are the top four challenges facing federal prosecutors, according to many of those who've prosecuted such cases:
1. "The law"
Under federal law, prosecutors need to prove two things: (1) it was "unreasonable" for Wilson to believe Brown posed a threat to him or the public, and (2) Wilson "willfully" deprived Brown of his constitutional rights.
"It's hard enough to prove willfulness to a jury when an officer beats a handcuffed suspect," said Rachel Harmon, a former Justice Department official who prosecuted several cases of excessive force by police. "It is much more difficult still when an officer uses force in an ongoing encounter with an unrestrained … suspect, even if that person is unarmed."
Reasonableness comes "from the perspective of a reasonable officer on the scene, rather than with the 20/20 vision of hindsight," a federal judge told jurors in a 2010 case in New Orleans that ultimately acquitted an officer who fatally shot an unarmed man.
That analysis must also consider "that police officers are often forced to make split-second judgments in circumstances that are tense, uncertain, and rapidly evolving," U.S. District Judge Lance Africk said then.
Federal investigators will also be taking a close look at Wilson's background and any personal views that could have impacted his decision-making when he encountered Brown.
In Ferguson, "even if [Wilson] was wrong about the amount of force that was necessary, if it was reasonable given all of what he was confronting at the time, then he can't be charged," said William Yeomans, who spent 26 years prosecuting civil rights cases at the Justice Department.
2. "Issues of proof"
In cases of excessive force, "You may have issues of proof," and there are "certain limitations," the current federal prosecutor nominated to replace Holder said more than a decade ago.
So prosecutors must often rely on eyewitness accounts. But such testimony "can be particularly problematic," Yeomans said, because eyewitnesses regularly have "very different" and inaccurate "pictures of what went on" during a chaotic incident.
It's "absolutely" an issue in the Ferguson case, he said.
In fact, at least one witness in Ferguson said Brown was shot "with his arms up in the air." But police claimed Brown was shot in the wake of a struggle for Wilson's gun and only after Brown started advancing toward Wilson.
Because the police claim is "a plausible scenario," it's "hard for a jury to think about sending Officer Wilson to jail," Yeomans said.
Brown family attorney Ben Crump, however, said, "People get arrested with far less evidence," insisting eyewitness testimony and "physical evidence" in the Ferguson case support charges against Wilson.
3. "Strong presumption in favor of law enforcement"
"There is a strong presumption in favor of law enforcement" when deciding whether to charge a police officer, Yeomans said. "And it is a risky business to be too proactive in second-guessing their instantaneous choices."
Both the law and juries give officers a lot of so-called "leeway" in that regard.
"Juries will give the police officers a significant benefit of the doubt," said Michael Magner, a former assistant U.S. attorney who helped prosecute the 2010 case in New Orleans.
The lawyer for the Brown family, Benjamim Crump, said the high bar for indicting cops is even more pronounced at the local grand jury level.
"When you got the local prosecutor sitting in judgment of the local police, they normally don't indict," Crump told ABC News. The justice system "gives all the favor to the police officers and does nothing for the citizens."
4. "Selective leaking" and "public opinion"
Holder has condemned the "selective leak" of certain information in the case, saying it is "harmful to the process."
Yeomans said the release of case information outside a grand jury room can have an impact on what happens inside the room.
Yeomans took particular issue with the official release of a video showing someone identified as Brown allegedly stealing cigars from a convenience store minutes before the fatal encounter with Wilson.
At the time, police insisted they "had to release" the video in the interest of transparency and because they received too many "freedom of information requests" from news outlets.
Still, many leaks – such as details of secret witness interviews and autopsy reports – have been favorable to Wilson, and that "tends to affect the way that grand jurors approach the situation," Yeomans said.
So what's next if federal charges don't happen?
In addition to its criminal investigation of Wilson, the Justice Department has launched a separate civil probe into the entire Ferguson police department, trying to determine whether officers routinely engage in a "pattern or practice" of unlawful and discriminatory policing.
Officers there have allegedly been more likely to stop and arrest a black driver than a white driver.
Depending on what federal investigators conclude and how city officials respond, a federal court could demand Ferguson police make sweeping changes.
Ferguson Mayor James Knowles told the St. Louis Post-Dispatch his city has "nothing to hide" and will cooperate with the federal investigation, hoping to restore confidence in the police force.
"The real goal" of such probes "is to effect some sort of systemic change that will prevent such incidents from occurring in the first place," Lynch said in 2000 – long before much of the nation had even heard of Ferguson.