In this review, we make an attempt to compare the characteristics and applications of red and near infrared cyanine and squaraine dyes used for biological research, biomedical assays, and high-throughput screening. While the favorable photophysical properties of cyanine dyes makes them predestined as covalent labels, the environmentally sensitive squaraine dyes are utilizable as both florescent probes and labels. Reducing the aggregation tendencies of these dyes in aqueous media seems to be one of the most promising ways to improve their brightness, fluorescence lifetimes, and photostability. Indolenine-based squaraines including ring-substituted squaraines exhibit great potential for the design of bright and sensitive fluorescent probes and labels with increased photostability.