Direct reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) provides an invaluable resource for regenerative medicine, enabling the generation of patient-specific cells of any lineage without the use of embryonic material. A variety of methods exist for iPSC derivation, all reliant upon manipulation of a select group of transcription factors. We compare the currently reported protocols, identify essential steps common to these methods, and suggest minimal criteria for defining fully reprogrammed cells. In addition, specific procedures aimed to optimize reproducible iPSC derivation are presented, with an emphasis on standardization of certain parameters for accurate comparison between independent experiments.