After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies.