The molecular mechanisms leading to spontaneous mutations have so far not yet been clarified experimentally. We mns~ point out that the concept of "spontaneous mutation" is in itseff problematic, for we have no conclusive evidence as to whether these genetic changes are in fact spontaneous, in other words, whether they follow the statistical rules of reduplication errors, or whether they are brought about by the influence of cell metabolism, the absence or alteration of enzymes such as polymerases, of mutagenic substances, or by the environment as such. It might be possible, for instance, that under certain circumstances changes in temperature or ionic strength may activate or inactivate important enzymes or even convert one isozymic form to another. Peroxides or intermediately formed radicals or methylating enzymes might attack nucleic acid bases in a manner which resembles the action of radiation or alkyating agents. The small content of UV rays in ordinary hght might also play a role in spontaneous mutations, at least in bacteria at the so-called hot spots. Here the well-known formation of thymidine dimers, or in small amounts of cytosine dimers, followed by deamination to uracil, should be mentioned. In addition it is conceivable that the very small amount of beta or gamma rays from isotopes incorporated into the cell might be important. This hypothesis is supported by the fact that mutation frequency increases with the time of storage even when no nucleic acid metabohsm is observed, as is the ease with viruses, phage, or resting bacteria. It is perhaps worth mentioning that, for example, thymine-hydroxyhydroperoxide formed after irradiation of nucleic acids remains attached as such to the nueleotide chain. Reduplication or transcription of DNA with such an altered base could probably not proceed normally. Finally the integration into the genome of the cell of some as yet unknown viruses could be the cause of mutation. We must always take into consideration that the initiation of mutation can occur in non-dividing cells.