Even in modern times, the popularity level of medicinal plants and herbal medicines in therapy is still high. The World Health Organization estimates that 80% of the population in developing countries uses these types of remedies. Even though herbal medicine products are usually perceived as low risk, their potential health risks should be carefully assessed. Several factors can cause the toxicity of herbal medicine products: plant components or metabolites with a toxic potential, adulteration, environmental pollutants (heavy metals, pesticides), or contamination of microorganisms (toxigenic fungi). Their correct evaluation is essential for the patient’s safety. The toxicity assessment of herbal medicine combines in vitro and in vivo methods, but in the past decades, several new techniques emerged besides conventional methods. The use of omics has become a valuable research tool for prediction and toxicity evaluation, while DNA sequencing can be used successfully to detect contaminants and adulteration. The use of invertebrate models (Danio renio or Galleria mellonella) became popular due to the ethical issues associated with vertebrate models. The aim of the present article is to provide an overview of the current trends and methods used to investigate the toxic potential of herbal medicinal products and the challenges in this research field.