Single particle reconstruction using Cryo-Electron Microscopy (cryo-EM) is an emerging technique in structural biology for estimating the 3-D structure (density) of protein macromolecules. Unlike tomography where a large number of images of a specimen can be acquired, the number of images of an individual particle is limited because of radiation damage. Instead, the specimen consists of identical copies of the same protein macro-molecule embedded in vitreous ice at random and unknown 3-D orientations. Because the images are extremely noisy, thousands to hundreds-of-thousands of projections are needed to achieve the desired resolution of 5Å. Along with differences of the imaging modality compared to photographs, single particle reconstruction provides a unique set of challenges to existing computer vision algorithms. Here, we introduce the challenge and opportunity of reconstruction from transmission electron micrographs, and briefly describe our contributions in areas of particle detection, contrast transfer function (CTF) estimation, and initial 3-D model construction.