The importance of plants and other natural reserves as sources for biologically important compounds, particularly for application in food and medicine, is undeniable. Herein we provide a historical context of the major scientific research programs conducted in Australia that have been aimed at discovering novel bioactive natural products from terrestrial plants. Generally speaking, the main approaches used to guide the discovery of novel bioactive compounds from natural resources have included random, ethnobotanical and chemotaxonomic strategies. Previous Australian plant natural product research campaigns appear to have lacked the use of a fourth strategy with equally high potential, namely the ecologically guided approach. In addition, many large studies have sampled plant material predominantly from tropical regions of Australia, even though arid and semi-arid zones make up 70% of mainland Australia. Therefore, plants growing in arid zone environments, which are exposed to different external stressors (e.g. low rainfall, high ultraviolet exposure) compared with tropical flora, remain an untapped reservoir of potentially novel bioactive compounds. Research of Australian arid zone plants that is ecologically guided creates a new opportunity for the discovery of novel bioactive compounds from plants (and potentially other biota) for application in health care, food and agricultural industries.