This review describes recent developments in analysing the influence of radio-frequency electromagnetic fields (RF-EMFs ) on biological systems by monitoring the cellular stress response as well as overall gene expression. Recent data on the initiation and modulation of the classical cellular stress response by RF-EMFs, comprising expression of heat shock proteins and stimulation of stress-activated protein kinases, are summarised and evaluated. Since isothermic RF-EMF exposure is assumed rather than proven there are clear limitations in using the stress response to describe non-thermal effects of RF-EMFs. In particular, further experiments are needed to characterise better the threshold of the thermal heat shock response and the homogeneity of the cellular response in the whole sample for each biological system used. Before then, it is proposed that the absence of the classical stress response can define isothermal experimental conditions and qualifies other biological effects of RF-EMFs detected under these conditions to be of non-thermal origin. To minimise the probability that by making this assumption valuable insights into the nature of biological effects of RF-EMFs could be lost, proteotoxic non-thermal RF-EMF effects should also be monitored by measuring activities of labile intracellular enzymes and/or levels of their metabolites before the threshold for the heat shock response is reached. In addition, non-thermal induction of the stress response via promoter elements distinct from the heat shock element (HSE) should be analysed using HSE-mutated heat shock promoter reporter constructs. Screening for non-thermal RF-EMF effects in the absence of a classical stress response should be performed by transcriptomics and proteomics. Recent approaches demonstrate that due to their high-throughput characteristics, these methods inherently generate false positive results and require statistical evaluation based on quantitative expression analysis from a sufficient number of independent experiments with identical parameters. In future approaches, positive results must be confirmed by independent quantitative methods and should also be evaluated in vivo to prove possible non-thermal effects of RF-EMFs on living beings. If successful, this strategy should contribute to identification of new underlying molecular mechanisms of interaction between RF-EMFs and living beings distinct from absorption of thermal energy.