The guanidine functional group is an important structural motif in synthesis with a wide range of interesting properties. Guanidines are frequently found in bioactive compounds; both from natural sources or from synthetic origin, these compounds are considered fundamental entities in medicinal chemistry. The relevance of these compounds fosters the efforts to explore new methodologies for the synthesis of substances based on the guanidine core. The aim of this review is to provide a survey of the types of reactions used to prepare these classes of compounds. Given the vast number of contributions to this topic, we have focused on the achievements made in the last five years and, in particular, in the synthesis of biologically relevant heterocyclic guanidine-derivatives.