Sequence stratigraphy remains the foremost methodology used to describe the stratigraphic record and to interpret the controls on deposition; yet, it relies on long-standing assumptions that few studies have sought to validate. Here, we present results from testing hypotheses related to the deep-water depositional sequence model by revisiting the seismic-based type locality: the Mississippi Fan, in the central Gulf of Mexico. By independently testing the relationship between cycles of relative sea-level change and those of sedimentation, we demonstrate that >98% of Neogene-Quaternary deep-water sequences do not accumulate in a manner prescribed by long-held sequence stratigraphic conventions. Instead, over the past 5.5 Myr, sequences show a temporal mismatch in frequency, phase, and amplitude with cycles of relative sea-level change, a concept we refer to as stratigraphic aliasing. Divergences are attributed to variable rates of sedimentation, which were responsible for creating cycle frequencies that were both higher and lower than those of relative sea-level change, and that resulted in two modes of Mississippi Fan accumulation: lower average sedimentation rates in older sediments, and an opposite trend in younger successions. The latter mode occurred ~2.2 Myr after the onset of North American glaciation, a period marked by significant continental drainage reorganization and salt-tectonic deformation. Based on our conclusions, we recommend that the future of sequence stratigraphy be rooted firmly in assessing the reproducibility of preexisting spatiotemporal predictions and in the rigorous use of multiple working hypotheses.