Global studies focusing on climate extremes in urban areas, specifically in Mexico, have not been approached with a sufficient level of detail, despite considerably increased risks for both infrastructure and human society. Based on 14 climate indices proposed by the Expert Team on Climate Change Detection and Indices (ETCCDI) and the application of the nonparametric Mann-Kendall and Sen’s slope tests, the observed trends of climate extremes in 16 urban areas in Mexico from 1980 to 2010 were analyzed. The results show that climate conditions over most cities of Mexico are changing, as indicated by a warming trend during the study period. Significant increases were detected in the annual average maximum temperature (TMX) and the annual average minimum temperature (TMN). There is no clear trend that the warmest days (TXx) are increasing, but the annual number of warm days (TX90p) and summer days (SU) has increased, and the cold days (TX10p) have decreased. Associated with these changes are concomitant decreases in fewer coldest nights (TNn), an increase in the percentage of days with warm nights (TN90p) and tropical nights (TR), and a decrease in the number of frost days (FD). In contrast, the analysis reveals a statistically significant decrease in the mean temperature and the amount of warm days in Mexico City, which could be associated with the increasing trend of atmospheric pollution and the continuous smoke and ash emissions from the volcano Popocatepetl, which disperse incoming solar radiation and reduce radiative forcing. Climate change indices based on daily precipitation data show positive trends in many cities. In general, an increasing trend in very wet days (R95p), a number of very heavy rainfall days ≥ 25 mm (R25), and the annual total wet days (PRCP) were observed. These results highlight the vulnerability of cities confronted with both global and local climate change and the importance of promoting effective local risk reduction measures as part of urban planning for city dwellers.