The standard paradigm of embryologic development and adult tissue reconstitution posits unidirectional, hierarchical lineages. The presumed mechanisms underlying these differentiative pathways are gene restrictions, such as methylation and heterochromatin formation, which are commonly described as irreversible. However, recent discoveries regarding multi-organ stem cells demonstrate that ‘true plasticity’exists, with cells of one organ turning into cells of other organs, including differentiative transformations that cross barriers between tissues derived from different primitive germ layers. These findings, along with earlier experiments into heterokaryon formation and longstanding recognition of reactive and neoplastic lesions in humans and animals, suggest that lineage pathways are not, in fact, unidirectional. Moreover, physiologic mechanisms of reversal of gene restrictions have been recognized. Therefore, in response to these observations, we suggest a new paradigm of cell plasticity, elucidating three guiding principles of ‘genomic completeness’,‘uncertainty of cell characterization’, and ‘stochastic nature of cell origins and fates’. These principles imply a change in the way data can be interpreted and could alter subsequent hypothesis formation. This new paradigm will hopefully lead us forward to a more flexible and creative exploration of the potential of adult vertebrate cells.