The largest accidental marine oil spill (4.9 million barrels) in the Gulf of Mexico (GoM) seabed (1600 m) caused by the sinking of the Deepwater Horizon oil rig in 2010, put to the test once again the resilient capacity of the pelagic and benthic realms of this Large Marine Ecosystem. Many are the ecological services provided by its waters (fisheries, tourism, aquaculture and fossil fuel reserves) to neighboring countries (US, Mexico and Cuba). However, the unprecedented volumes of hydrocarbons, gas and chemical dispersants (Corexit) introduced in the system, represent ecological stressors whose deleterious effects are still the subject of civil claims and scientific controversy. Presumably, the short scale effects were confined to the Gulf’s northeastern shallow waters, and the combined actions of weathering, biodegradation, and oil recovery left the system almost under pre-spill conditions. Unfortunately, surface and subsurface oil plumes were detected in the spill aftermath, and their dispersion trajectories threatened Mexico EEZ. Surface oil slicks were detected in the pristine waters of northern Yucatán, while subsurface oil plumes from the Macondo’s well blowout were dangerously advancing southwest towards key fishing grounds in the northwestern GoM. This disaster prompted the Mexican government to implement an ambitious ocean monitoring program adopting a bottom-up approach focused on building a base line for more than 42 physicochemical and biological variables for water, sediment and biota from the continental shelf-slope region of the NW GoM. Technological constraints have precluded systematic observations in the vast Mexican EEZ that could discriminate natural variability and oil seep emissions from antropic disturbances. Therefore, preliminary risk analyses relied on seasonal and historical records. Two years of field observations revealed subtle environmental changes in the studied area attributed to antropic disturbances. Waters maintained oligotrophic conditions and zooplankton and benthic infaunal biomass were also poor. Biomarkers in sediments and biota did not exceed EPA’s benchmarks, and sediment’s fingerprinting (δ¹³C) indicated marine carbon sources. Geomarkers revealed an active transport from the Mississippi towards the NW GoM of phyllosilicates bearing a weathered oil coating. Consequently, shelf and slope sediment toxicity begins to show an increasing trend in the region. The complexity of hydrocarbons bioaccumulation and biodegradation processes in deep waters of the GoM seems to indicate that meso-and large-scale observations may prove to be essential in understanding the capacity of the GoM to recover its ecological stability.