High concentration protein delivery is difficult to achieve for several protein pharmaceuticals due to low solubility. In this review, we discuss different types of low protein solubility, including low in vitro solubility, which is relevant to the formulation of protein pharmaceuticals. We also discuss different methods of measuring protein solubility with an emphasis on the method of inducing amorphous precipitation using ammonium sulfate. Finally, we discuss strategies for increasing protein solubility, including site-directed mutagenesis. Evidence from solubility-changing mutations in the literature indicate that some hydrophilic residues (aspartic acid, glutamic acid, and serine) contribute significantly more favorably to protein solubility than other hydrophilic residues (asparagine, glutamine, threonine, lysine, and arginine). These findings should prove useful especially in cases where protein structure is not known. In these cases, instead of targeting hydrophobic residues that are often buried, one could target hydrophilic residues that do not contribute favorably to protein solubility and replace them with hydrophilic residues that contribute more favorably.