Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.