Eastern black nightshade, Palmer amaranth, and common pokeweed are three hard to control weed species on the Eastern Shore regions of Virginia and Maryland. Herbicide resistance and lack of herbicide efficacy further complicate the job of controlling these weeds. Studies were conducted on each of these weeds in order to determine herbicide efficacy and potential herbicide resistance. In addition, the translocation and metabolism of 14C-glyphosate was studied in common pokeweed. This research identified a population of eastern black nightshade that was differentially sensitive to families of ALS-inhibiting herbicides, with tolerance to members of the sulfonylurea family, but controlled with herbicides of the imidazolinone family. A population of Palmer amaranth was found to be glyphosate-resistant, but herbicide programs were identified that could control this biotype in soybean and corn systems. Experiments on the fate of glyphosate in common pokeweed indicated that glyphosate does not readily translocate from treated foliage to other plant parts, which may contribute to shoot regeneration from taproots following glyphosate treatment. Taken together, this research highlights the important weed control issues, including resistant and perennial weeds in agronomic crops that have arisen in Eastern Shore agriculture. This work will help growers to better assess their particular control issues, and take appropriate steps to mitigate any problems.