I'm in a discussion with a confessional Lutheran pastor and he'd like me to explain how Isaiah 53--a common Protestant proof-text for penal substitution--lines up with Orthodox theology. (He's also asking about part of Isaiah 52, but I don't see any difficulties there; he must simply want to give the full context.)
I'm having a hard time providing him a solid answer, because some parts of this text seem to support, based on the straightforward reading, an innovative doctrine which the Church flatly denies.
I'll quote the whole Scripture passage at issue, with my comments and questions interspersed.
 Who has believed what we have heard?
And to whom has the arm of the LORD been revealed?
 For he grew up before him like a young plant,
and like a root out of dry ground;
he had no form or comeliness that we should look at him,
and no beauty that we should desire him.
These verses don't pose any problems.
 He was despised and rejected by men;
a man of sorrows, and acquainted with grief;
and as one from whom men hide their faces
he was despised, and we esteemed him not.
This verse is describing the reaction of other people to Christ, rather than God's view of him. But why is he "a man of sorrows" and "acquainted with grief"?
 Surely he has borne our griefs
and carried our sorrows;
yet we esteemed him stricken,
smitten by God, and afflicted.
This verse is just plain confusing. On the one hand, it is stated matter-of-factly that (1) Christ "has borne our griefs" and "carried our sorrows", and on the other it is added that (2) "we esteemed him stricken, smitten by God, and afflicted"--as if the first part involved an accurate evaluation and the second part a mistaken impression. Both (1) and (2) seem to be saying the same thing, though, so why the conjunction "yet"?
 But he was wounded for our transgressions,
he was bruised for our iniquities;
upon him was the chastisement that made us whole,
and with his stripes we are healed.
What does it mean for Christ to have been "wounded for our transgressions" and "bruised for our iniquities"? What was God doing if "upon [Christ] was the chastisement that made us whole" and "with his stripes we are healed"?
 All we like sheep have gone astray;
we have turned every one to his own way;
and the LORD has laid on him
the iniquity of us all.
What does it mean for "the LORD [to have] laid on [Christ] the iniquity of us all"?
 He was oppressed, and he was afflicted,
yet he opened not his mouth;
like a lamb that is led to the slaughter,
and like a sheep that before its shearers is dumb,
so he opened not his mouth.
 By oppression and judgment he was taken away;
and as for his generation, who considered
that he was cut off out of the land of the living,
stricken for the transgression of my people?
 And they made his grave with the wicked
and with a rich man in his death,
although he had done no violence,
and there was no deceit in his mouth.
These verses all say that Christ was viewed unfavourably and treated unjustly by those who arrested and killed him. If in "oppression and judgment he was taken away", was "his generation" in fact mistaken to have "considered that he was cut off out of the land of the living"? Was Christ actually "stricken for the transgression of [God's] people", or was that simply their erroneous conclusion given the horrors they saw visited on an innocent man?
 Yet it was the will of the LORD to bruise him;
he has put him to grief;
when he makes himself an offering for sin,
he shall see his offspring, he shall prolong his days;
the will of the LORD shall prosper in his hand;
In what sense and to what end "was [it] the will of the LORD to bruise [Christ]" and "[did] he put [Christ] to grief"?
 he shall see the fruit of the travail of his soul and be satisfied;
by his knowledge shall the righteous one, my servant,
make many to be accounted righteous;
and he shall bear their iniquities.
 Therefore I will divide him a portion with the great,
and he shall divide the spoil with the strong;
because he poured out his soul to death,
and was numbered with the transgressors;
yet he bore the sin of many,
and made intercession for the transgressors.
How did Christ "bear [the] iniquities [of many]"/"[bear] the sin of many"? How does this act fit in with "[making] intercession for the transgressors"?