IL-17A-producing CD4 T helper cells (Th17) are crucial for the development of inflammatory and autoimmune diseases and thus are exploited for clinical immunotherapies. Emerging evidence suggests Th17 cells are heterogeneous and able to adopt both pathogenic and non-pathogenic phenotypes which are shaped by environmental and genetic factors. On one hand, IL-6 in concert with TGFβ1 can induce non-pathogenic Th17 cells (non-pTh17), which are not effective in inducing tissue inflammation. On the other hand, IL-6, IL-1β with IL-23 induce pathogenic Th17 cells (pTh17) to induce immune pathologies in various tissues. Th17 cells could be both pathogenic and non-pathogenic in a content-dependent manner in vivo. Understanding how the generation and pathogenicity of pTh17 cells are regulated will aid us to devise more effective immunotherapy. In this review, we summarize recent advances in the differentiation and regulation of Th17 cells especially pTh17 cells in vitro and in vivo. The emerging results revealing the specific molecular control of pTh17 cells are highlighted.