In the last years many efforts have been made to develop sunflower cultivars showing important agronomical characteristics such as herbicide resistance. These approaches have been focused mainly on resistance to herbicides with the same mode of action that is acetohydroxyacid synthase (AHAS) inhibitors. To date four induced and natural AHAS mutations have been found that confer resistance to these herbicides and many of these alleles are being used for the production of sunflower hybrids resistant to herbicides and to develop different non-transgenic technologies for weed control. However little is known about the bases of non-target-site-based resistance (NTSR) developing cross-resistance to herbicides with different modes of action in sunflower. These mechanisms diminish the number of active herbicide molecules that reach the target and are generally polygenic. Elucidating the nature of NTSR would allow evaluating maximal efficiency conditions for the herbicide and would enable to establish weed management strategies in sunflower crop. Nowadays mining of NTSR genes can be more easily accomplished taking advantage of up-to-date omics-based approaches: high-throughput techniques involving genomics transcriptomics proteomics and metabolomics. Considering the difficulties in the discovery of new compounds with a broad spectrum of weed control it results essential to broaden the use of former herbicides which are highly efficient and ecologically desirable. Full understanding of NTSR mechanisms in sunflower would allow detecting specific genes potentially useful as biotechnological tools for the phytoremediation of herbicides and modern plant breeding.