Organic dyes that absorb and emit in the near-infrared (NIR) region are potentially noninvasive, high-resolution, and rapid biological imaging materials. Indolizine donor-based cyanine and squaraine dyes with water-solubilizing sulfonate groups were targeted in this study due to strong absorptions and emissions in the NIR region. As previously observed for nonwater-soluble derivatives, the indolizine group with water-solubilizing groups retains a substantial shift toward longer wavelengths for both absorption and emission with squaraines and cyanines relative to classically researched indoline donor analogues. Very high quantum yields (as much as 58%) have been observed with absorption and emission >700 nm in fetal bovine serum. Photostability studies, cell culture cytotoxicity, and cell uptake specificity profiles were all studied for these dyes, demonstrating exceptional biological imaging suitability.