Idiosyncratic drug reactions (IDRs) of a hepatic origin are a major health concern and a notoriously difficult challenge for the pharmaceutical industry. These types of adverse events are rare, with a typical occurrence of 1 in 100 to 1 in 100,000 patients. Typical adverse outcomes are most likely statistically impossible to predict in traditional preclinical safety studies or clinical trials. Unfortunately, these reactions can pose a significant risk to the public health, resulting in devastating consequences such as irreversible liver injury, liver transplantation and fatality. This review provides many examples of experimental efforts that are underway for a better understanding of molecular events that may be responsible for IDRs. A list of existing hypotheses for IDRs is also provided, each with current literature examples or supporting evidence. The possibilities for developing suitable animal models for the prediction and characterisation of IDRs are elaborated, especially for a drug-inflammation interaction rat model of hepatic IDR. The need for predictive biomarkers of IDR is addressed, with the exploration of some possible candidates. Finally, the use of primary human hepatocyte culture systems is explored as an in vitro system, with application for providing an increased mechanistic knowledge of IDR. Several examples of informative studies on the nature of IDRs that employ toxicogenomic and proteomic technologies are summarised.