For over 25 years a major effort in electron microscopy of macromolecules has been the determination of the three dimensional structure from the two-dimensional electron micrographs of such specimens. Great success has been realized when the macromolecule or complex takes the form of an array such as a 2D crystal (1,2), a helical structure (3,4) or one with icosahedral symmetry (5,6). However, for molecules which do not form such arrays, and in the limit only exist as single particles, a number of challenges have had to be addressed. No easy averaging of noisy low dose images is possible due to the lack of lateral and rotational symmetry. Random unknown orientations of the particles have to be determined, a process exacerbated by noise if low dose images are used as input. Alternatively, higher dose images result in radiation-induced structural alterations of the macromolecule.