It is rare that such a diverse array of applications can be realized from a single basic molecular unit, however, such is the power of the tetrapyrrolic macrocycle motif. Indeed, their potential in areas such as chemical dyes, optical sensors, optoelectronics, and biomedical agents is a function of their rich electronic and optical properties. While the naturally occurring porphyrins and the synthetic phthalocyanines have been extensively studied, the related tetraazaporphyrins or porphyrazines remain comparatively underdeveloped. Since porphyrazines maintain a unique position in this family: analogous derivatives are virtually inaccessible for the porphyrins, and direct fusion of heteroatomic substituents onto the porphyrazine β-positions results in a more pronounced effect compared with the substitution of an equivalent group onto the benzenoid rings of the phthalocyanine; a driving force exists to further explore the synthesis and applications of these novel macrocycles. This review will provide a historical overview of the synthetic strategies towards functionalized porphyrazines and describe new strategies towards the preparation and applications of heteroatom-appended porphyrazines, particularly in the context of their multimetallic complexes, catalysis, surface chemistry, and as biomedical agents.