The diverse chemical structures of inositol pyrophosphates attract growing interest toward this class of small molecule messengers. However, their highly charged nature, the lack of a chromophore or a fluorophore, their close structural relatedness, and the complexity of their metabolism pose serious challenges to inositol pyrophosphates studies. Here, we summarize how researchers have begun to overcome these challenges and how recent experimental advances are propelling inositol pyrophosphate research into the future.