T-helper cells integrate signals from their T-cell receptor, co-stimulatory molecules and cytokine receptors to polarize into effector T-helper subsets with specialized functions in antigen clearance or tolerance. To this end, antigen presenting cells and the local microenvironment tailor effector T-helper cells to respond appropriately to microbial challenges. These challenges comprise protection from pathogens on the one hand and tolerance for the commensal microbiota on the other hand. To accomplish these complex tasks, the host immune system needs to be highly specialized and stringently regulated. In this viewpoint article, we will concentrate on how microbes shape human T-helper cell responses and how this could relate to the emergence of chronic inflammatory diseases. Understanding the intricate communication between adaptive immunity and microbes will be important for the rational design of novel immunomodulatory therapies and also for anticipating infectious complications upon therapeutic intervention with cytokine depleting therapies, such as biologicals in dermatology.