Secondary failure is defined as a deterioration of glucose control in patients with Type 2 diabetes on oral antidiabetic drugs (OAD), mainly due to the progressive decline in beta-cell function and reduction in insulin secretion. The consequent hyperglycemia is the most important determinant for the development of microvascular and macrovascular complications, so that an early recognition of this phenomenon can improve long-term outcomes. The recent lowering of target glycosylated hemoglobin (HbA1c) levels by international guidelines not only emphasises the importance of tight glycemic control, but also means that secondary failure to OAD will occur much sooner and is almost unavoidable. Accordingly, in the last years, new different therapeutic strategies were explored to improve the treatment of this condition. The aim of this review is to examine current approaches for treating patients with secondary failure, barriers to achieving and maintaining glycemic control, and recent evidence for emerging therapies which may represent a valid therapeutic option in subjects failing on oral hypoglycemic agents by acting mainly, but not only, at a beta-cell level. In particular, we will focus on the co-administration of OAD plus a novel drug class known as incretin mimetics (e.g. exenatide and liraglutide), which target insulin secretion, and on thiazolidinediones, which act on insulin resistance. Only incretin-mimetics have a lowering HbA1c action, due to the improvement in beta-cell function, which is coupled to significant weight loss. Even if these new options seem to improve the outcome of secondary failure, further investigation is needed to confirm positive results in the long term.