Herbivorous insects have the capacity to develop behavioral, physiological, and biochemical resistance mechanisms in response to chemical selection pressures. Among natural insect-plant associations, there are several cases of target-site insensitivity to and enhanced metabolism of plant allelochemicals. There are also known instances of physiological defenses such as extra rapid excretion or storage of toxic compounds. Multiple defenses seem to be prevalent in natural insect-plant interactions that involve toxic compounds, possibly reflecting the long time these interactions have had to evolve compared to insect-synthetic insecticide interactions. Synthetic insecticides were introduced about 45 years ago. Until recently they have been used as single-active-component preparations. As such, they have been and are very effective in producing insect populations with enhanced detoxification ability and target-site insensitivity. Most insecticide-resistant insect populations have one major defense mechanism. This feature makes the synthetic insecticides very useful tools for studies of insect defenses against toxic chemicals. Information gained from studies with insecticides can shed light on the capabilities of insects to adapt to toxicants in their environment. In assessing the validity of work with synthetic insecticides for natural systems, the fundamental differences between these substances and allelochemicals, and in their presentation to the insects, must, however, be considered. The prevalence of multiple defenses and reliance on modified physiological processes in natural interactions may reflect different properties of the natural chemicals in being generally highly biodegradable and often less acutely toxic than synthetic insecticides. In many cases, the plant allelochemicals are presented to the insects as mixtures. It is, however, to be expected that pest insects will evolve effective multiple defenses against synthetic insecticides. About 20% of all resistant populations have already developed multiple defenses, in most cases combinations of enhanced metabolism and target-site insensitivity. This implies that current crop protection practices need to be modified to ensure the continued usefulness of synthetic insecticides. To achieve this, it is important to study intensively not only insect-insecticide interactions but also the interactions operating in natural insect-plant associations.