Photons are precious in single-molecule fluorescence microscopy. As such, over the past couple decades the single-molecule community has embraced concepts from classical estimation and detection theory to optimize information recovered from each detected photon. Recent work in our group and others have shown that a quantum theoretic framework for estimation and detection provides even more fundamental insights by facilitating additional optimization over all possible measurements allowed by quantum mechanics. In this talk I will present my group’s recent experimental and theoretical progress in this area.