Short interfering RNAs (siRNAs) are the most commonly used RNA interference (RNAi) triggers. They hold promise as potent therapeutic tools, as demonstrated by recent successful in vivo experiments. However, in addition to triggering intended sequence-specific silencing effects, the reagents of RNAi technology can often cause side effects, including immunological off-target effects. The cellular sensors of foreign RNA, such as RIG-I or Toll-like receptors, involved in innate immune antiviral responses, are activated by RNAi reagents. Stimulation of these pathways results in changes in the cellular transcriptome and proteome that can lead to the inhibition of cell division and growth and eventually apoptosis. An additional undesired effect in the context of research applications may be the misinterpretation of experimental results. To date, a number of the specific features of siRNA structure, sequence and delivery mode that are responsible for these effects have been identified. This knowledge may be helpful in designing safer gene-silencing reagents. In this article we discuss the recent developments in the field of non-specific toxic effects caused by RNAi triggers and their delivery vehicles. These data are critically discussed and evaluated, taking advantage of relevant information compiled in the recently launched RNAimmuno database (http://rnaimmuno.ibch.poznan.pl).