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Weeds that usually grow in non-agricultural areas have become increasingly common invading perennial crops. Species of the genus <i>Filago</i>, in addition to invading Spanish olive groves, have developed certain levels of natural tolerance to the acetolactate synthase (ALS) inhibiting herbicide flazasulfuron. The objective of this study was to determine the level and the mechanism involved in the tolerance to flazasulfuron in <i>Filago pyramidata</i> L., which occurs in olive groves of southern Spain, as well as to identify possible cross- or multiple-tolerances by evaluating alternative herbicides for its control. A population resistant (R) to flazasulfuron and a susceptible (S) one of <i>Conyza canadensis</i> were used as references. The accessions of <i>F. pyramidata</i> presented LD₅₀ values (from 72 to 81 g active ingredient (ai) ha⁻¹) higher than the field dose of flazasulfuron (50 g ai ha⁻¹), being 11–12.5 times more tolerant than the S population of <i>C. canadensis</i>, but less than half the R population (170 g ai ha⁻¹). Enzymatically, <i>F. pyramidata</i> was as sensitive to flazasulfuron (I₅₀ = 17.3 μM) as the S population of <i>C. canadensis</i>. <i>Filago pyramidata</i> plants treated with flazasulfuron, combined with 4-chloro-7-nitro-2,1,3-benzoxadiazole, had a growth reduction of up to 85%, revealing the participation of glutathione-S-transferases in herbicide metabolism. <i>Filago pyramidata</i> presented cross-tolerance to the different chemical groups of ALS inhibitors, except triazolinones (florasulam). Synthetic auxins (2,4-D and fluroxypyr) presented good control, but some individuals survived (low multiple resistance). Cellulose synthesis, 5-enolpyruvylshikimate-3-phosphate, 4-hydroxyphenylpyruvate dioxygenase, protoporphyrinogen oxidase, photosystem I, and photosystem II inhibitor herbicides, applied in PRE or POST-emergence, presented excellent levels of control of <i>F. pyramidata.</i> These results confirmed the natural tolerance of <i>F. pyramidata</i> to flazasulfuron and cross-tolerance to most ALS-inhibiting herbicides. The mechanism involved was enhanced metabolism mediated by glutathione-S-transferases, which also conferred low multiple tolerance to synthetic auxins. Even so, herbicides with other mechanisms of action still offer excellent levels of control of <i>F. pyramidata.</i>