Summer Glau as Jessica Drew, codename Spider-Woman.  She’s been enhanced with spider DNA, raised by HYDRA, and trained by the Taskmaster, and in the pilot, she turns and starts working for SHIELD with Dum-Dum as her handler.  A little Alias, a little Girl With The Dragon Tattoo.  Summer has the looks and the action chops, the nerdfolk love her, and Joss has her number and takes care of his people.

Of course, once you cast one Whedon regular, you start thinking about others who could use the work.  Any ideas, true believers?  To get you started . . . Ron Glass as Gabe Jones, although I don’t know whether he’s better played as the same Gabe from Cap’s WWII team (either age suppressed or appropriately made-up to add 25 years), or as Gabe Jr.  I wouldn’t turn down Morena Baccarin as Valeria de Fontaine.