Directed by William Arntz, Mark Vicente and Betsy Chasse, What the #$*! Do We Know is made up of three distinct elements: documentary footage, live-action story elements, and animation effects. Both the 3D animation and other effects sequences, which totaled 300 effects shots, were overseen by visual effects supervisor Evan Jacobs, and executed by Mr. X in Toronto, Lost Boys Studios in Vancouver, and Atomic Visual Effects in Cape Town, South Africa.

The most daunting effects challenge was just developing the stylized look of the animated sequences, in particular, all of which had to entertain while also illustrating complex scientific concepts. "If you were to just read the script," Jacobs said, "you would think, 'Okay, this is like Discovery Channel or the Science Channel.' But Will Arntz was very clear that he wanted it to be bold and stylized. He didn't want boring science documentary stuff. He wanted it to be part of the story."

One of the animated sequences, created by Atomic Visual Effects, represents a camera traveling through the interior of the brain. "We took a lot of liberties to make the environment look more cool than the real interior of the brain would look," said Jacobs. "We took all the matter away, except for the nerve cells, creating a forest of electrically charged nerve cells." Though the look was more stylized than anatomically correct, the modeled nerve cells were taken from photographs of real nerve cells. "We went with a shader approach to create glowing, self-illuminated nerves -- which meant we didn't have to add a lighting element to this fairly heavy nerve geometry. Those were the kinds of cheats we did to make it more economical."

Motion control was used for a live-action sequence in which Amanda comes face to face with other versions of herself inside the lobby of a movie theater and on a sidewalk outside. "It wasn't a new trick," Jacobs said, "but on a low-budget, and with the tight locations we chose, it was a challenge. We had to put her in five different outfits, and make sure she wasn't intersecting herself in this big long shot. We covered 500-600 feet in the shot -- and it was overcranked, too, which added complexity. Again, it's not that this hasn't been done before; but to do it at this level of production was a feat." All of the motion control material was shot over two nights, by General Lift.

In a dream sequence, Amanda finds herself on a fantasy island. "This sequence illustrates a story about when Columbus and his ships arrived in the West Indies," Jacobs explained. "Because the Indians had never seen clipper ships before, they literally couldn't see them on the horizon. But then the shaman looks out to sea and sees the ripples made by the ships -- and, eventually, he sees the ships themselves. He's the only one with an open enough mind to see them." In the film, the shaman approaches Amanda on the beach, then points out to sea, where the clipper ships suddenly appear. "When I read the script, I thought, 'Okay, we'll go to a beach somewhere for this.' But, due to Marlee's schedule, we couldn't get her after the shoot in Portland. So we shot her on greenscreen, and just put in background plates. It doesn't seem as if that would be too hard, but it was amazingly difficult to find good stock backgrounds. So we had to shoot the backgrounds. We wound up shooting the backgrounds in South Africa -- since we were already there, doing some post work."

At the time the greenscreen of Matlin was shot, the backgrounds were still undetermined -- which meant the ultimate lighting scenario was unknown. "Fortunately, the gods were smiling on us that day," said Jacobs. "It was a little overcast, so we had flat lighting and we had some latitude when we put the backgrounds in. Basically, we were in a parking lot in Portland, shooting this thing -- but it works in the movie." Atomic composited the dream and theater sequences.