Herbicides have made significant contributions to modern agriculture by offering exceptional weed management in crops and also facilitate no-till crop production to conserve soil and moisture. However, repeated field applications of herbicides with the same mechanism of action resulted in selection of herbicide-resistant weeds. A total of 403 confirmed herbicide-resistant weed biotypes have been documented to date (129 dicots and 89 monocots) to 21 of the 25 known herbicide sites of action [1]. Weed Science Society of America (http//www.wssa.net) defines herbicide resistance as the inherited ability of a plant to survive and reproduce following exposure to a dose of herbicide normally lethal to the wild type. In the presence of continued selection pressure (application of herbicides with the same mode of action), the resistant plants increase in frequency over time (generations) [2], thereby transforming a population dominated by individuals resistant to that herbicide.Several factors govern the rate at which the resistant individuals (alleles) become dominant in the population [3]. Genetic factors, such as the initial frequency of resistant alleles present in the population, the dominance relationships among the alleles and fitness cost of the resistance gene(s) can significantly influence evolution of resistance to herbicides. Other factors, such as biology of weed species (e.g. life cycle, seed production capability, mating system), the herbicide and target site properties (chemical structure, herbicide-target site interactions and residual activity), herbicide dose and application performance can impact dynamics of herbicide resistance evolution, as well. This review focuses on how genetic factors influence the evolution and spread of herbicide resistance in weeds and how herbicide use pattern can determine the genetics of herbicide resistance. Additionally, how this information can be useful in both proactive and reactive management of herbicide-resistant weeds is also discussed. Monogenic Target Site Resistance and Polygenic Non Target Site ResistanceMechanisms which confer resistance to herbicides can be categorized into: a) target site resistance (TSR) and non-target site resistance (NTSR). In TSR, mutation(s) in the target site of herbicide results in insensitive or less sensitive herbicide target protein [3], and in essence, involves alteration of the target-site gene (monogenic) [4]. NTSR results from non-target site alterations endowing reduced herbicide uptake/ translocation, increased rates of herbicide detoxification, decreased rates of herbicide activation or sequestration of the herbicide [5]. NTSR, especially if involved herbicide detoxification by cytochrome P450 monooxygenases, is usually governed by many genes (polygenic) and may confer resistance to herbicides with other modes of action [4,6]. However, glutathione S-transferase (GST)-mediated NTSR to triazines in velvetleaf is inherited as a single nuclear gene [7].Herbicide resistance conferred by a single gene with major effect can sprea...